Estrogen receptor modulators

ABSTRACT

Estrogen receptor-modulating pyrazole compounds are described in addition to methods and compositions for treating or preventing estrogen receptor-mediated disorders. The compounds described have been found to have unexpected and surprising activity in modulating estrogen receptor activity. Thus, the compounds of the present invention have utility in preventing or treating estrogen receptor-mediated disorders such as osteoporosis, breast and endometrial cancers, atherosclerosis, and Alzheimer&#39;s disease.

1 CROSS REFERENCE TO RELATED U.S. PATENT APPLICATIONS

[0001] The present application claims priority under 35 U.S.C. § 119(e)from co-pending provisional U.S. patent application serial number60/095,772, which is incorporated herein by reference in its entiretyand for all purposes.

2 BACKGROUND OF THE INVENTION

[0002] 2.1 Field of the Invention

[0003] The present invention relates to compounds that have biologicalactivity with respect to estrogen receptors and to the use of suchcompounds to treat diseases and disorders related to estrogen receptoractivity. More particularly, the present invention provides selectiveestrogen receptor modulators (“SERMs”). The present invention thereforerelates to the fields of medicine, medicinal chemistry, biochemistry,and endocrinology.

[0004] 2.2 Background

[0005] Estrogen is a hormone critical to normal human development andfunction. Although estrogen is the predominant “sex hormone” in women,in whom estrogen controls the development of female sex characteristicsand the development and function of the reproductive system (Berkow,Beers et al 1997), it is also found in men (Gustafsson 1998). Womenproduce estrogen primarily in the ovaries; however, estrogen affects avariety of physiological functions in women including body temperatureregulation, maintenance of the vaginal lining, and preservation of bonedensity (Jordan 1998). In addition, estrogen provides additional effectsthat are related to its ability to modulate production of cholesterol inthe liver, as demonstrated by the reduced occurrence of atherosclerosisin women compared to men due in part to the reduction of low-densitylipoprotein (“LDL”) (Jordan 1998). Estrogen has also been implicated indelaying and/or reducing the severity of Alzheimer's Disease (Jordan1998).

[0006] Failure to produce estrogen has profound physiologicalconsequences in females. Failure to produce estrogen resulting fromincomplete or absent ovary development (Turner's Syndrome) causesdeficiencies in the skin, bone (e.g., severe osteoporosis), and otherorgans severely affecting the life of the afflicted individual (Dodge1995). In normal women, estrogen production falls sharply upon the onsetof menopause, usually at about 50 years of age. The effects of the lossof estrogen production include increased atherosclerosis deposits(leading to greatly increase incidence of heart disease), decreased bonedensity (osteoporosis), and fluctuations in body temperature amongothers (Jordan 1998). Often, the effects of reduced estrogen productionare addressed by hormone replacement therapy (Dodge 1995, Berkow, Beerset al 1997; Jordan 1998).

[0007] However, estrogen also has undesirable effects. In menopausalwomen, supplementation of estrogen is associated with alleviation of theabove-described unwanted effects. But, administration of estrogen isalso associated with increased risks for breast and endometrial canceras well as blood clots (Jordan 1998). The increased risk of endometrialcancer can be addressed by the administration of progesterone (or itssynthetic analog progestin) to reinitiate menstruation and thereby shedpotentially malignant cells, but many older women find this undesirable(Jordan 1998). Breast cancer, however, is by far the greater risk ofestrogen replacement therapy, affecting one woman in every 15 betweenthe ages of 60 and 79 (Jordan 1998).

[0008] Thus, for a long time the treatment options for the serioushealth problems caused by a failure to produce estrogen were limited andentailed severe risks. However, the discovery that some agents acted asestrogen agonists in some tissues (e.g., bone) and as an antagonists inother tissues (e.g., breast) provided hope that more effectivetreatments for estrogen loss could be found (Gradishar and Jordan 1997;Gustafsson 1998; Jordan 1998; MacGregor and Jordan 1998). Thc best knownof these so-called Selective Estrogen Receptor Modulators (“SERMs“),tamoxifen, has been demonstrated to have therapeutic utility in treatingand preventing breast cancer and lowering LDL concentrations; yet,without significant reduction bone density (Jordan 1998; MacGregor andJordan 1998). However, tamoxifen has been associated with endometrialcancer and venous blood clots (Jordan 1998; MacGregor and Jordan 1998).In addition, tumor resistance to tamoxifen can occur (MacGregor andJordan 1998).

[0009] Tamoxifen has been followed recently by newer SERMs, inparticular raloxifenSe, that promise to provide many of tamoxifen'sbenefits with fewer risks (Howell, Downey et al. 1996; Gradishar andJordan 1997; Gustafsson 1998; Jordan 1998; Purdie 1999; Sato, Grese etal. 1999). These newer SERMs, including idoxifene (Nuttall, Bradbeer etal. 1998), CP-336,156 (Ke, Paralkar et al. 1998), GW5638 (Willson,Norris et al. 1997), LY353581 (Sato, Turner et al. 1998) are part of thesecond and third generation of partial estrogen agonists/antagonists. Inaddition, a new generation of pure antiestrogens such as RU 58,688 (Vande Velde, Nique et al. 1994) have been reported. A large number ofadditional partial and pure estrogen agonist/antagonist compounds andtreatment modalities have reported recently Bryant and Dodge 1995;Bryant and Dodge 1995; Cullinan 1995; Dodge 1995; Grese 1995; Labrie andMerand 1 995; Labric and Merand 1995; Thompson 1995; Audia and Neubauer1996; Black, Bryant et al. 1996; Thompson 1996; Cullinan 1997; Wilson1997; Miller, Collini et al. 1999; Palkowitz 1999; Wilson 1999).

[0010] However, no one drug candidate has emerged to fill the needs ofwomen who require the benefits of estrogen replacement to liveproductive lives and/or treatments for estrogen-dependent cancers. Theefforts to develop better partial and pure estrogen agonists andantagonists has been aided by several recent developments, including thediscovery that human estrogen receptor has at least two isoforms (“ERα”and “ERβ”) and the crystal structure of ERα that have permittedhigh-resolution structure-activity relationship studies (Sadler, Cho etal. 1998). Recently, a study of the application of combinatorialsynthetic methods combined with three-dimensional structure-activityanalysis to develop SERMs having optimal therapeutic profiles wasreported (Fink, Mortensen et al. 1999). That study examined severalheterocyclic motifs (imidazoles, thiazoles, pyrazoles, oxazoles, andisoxazoles) and identified certain pyrazole motifs as being well suitedfor combinatorial development of SERMs. The relative bindingeffectiveness of the pyrazoles viz. the other motifs was based on itsability to carry four substituents in addition to polarity consideration(see p. 215). In particular, the study referred the capacity of thepyrazole motif to carry four substituents explained the bindingeffectiveness pyrazoles compared to the poor binding results found forthe oxazole, thiazole, and isoxazole motifs.

[0011] However, despite these recent advances no drug candidate hasemerged to fill the needs of women who require the benefits of estrogenreplacement to live productive lives and/or treatments forestrogen-dependent cancers. The present invention addresses theme andother needs.

3 SUMMARY OF THE INVENTION

[0012] The present invention provides pyrazole estrogen receptor agonistand antagonist compounds in addition to methods and compositions fortreating or preventing estrogen receptor-mediated disorders. Thecompounds described herein have been found to have unexpected andsurprising activity in modulating estrogen receptor activity. Thus, thecompounds of the present invention have utility in preventing ortreating estrogen receptor-mediated disorders such as osteoporosis,breast and endometrial cancers, atherosclerosis, and Alzheimer'sdisease.

[0013] In a first aspect, the present invention provides compoundshaving the structures:

[0014] and their pharmaceutically acceptable salts. R₁ and R₃ areselected independently from the group consisting of optionallysubstituted aryl and aralkyl. R₂ is selected from the group consistingof hydrogen, halo, cyano, nitro, thio, amino carboxyl, formyl, andoptionally substituted loweralkyl, loweralkylcarbonyloxy,arylcarbonyloxy, heteroarylcarbonloxy, cycloalkylcarbonyloxy,cycloheteroalkylcarbonyloxy, arakylcarbonyloxy, heteraralkylcarbonyloxy(cycloalkyl)alkylcarbonyloxy, (cycloheteroalkyl)alkylcarbonyloxy,loweralkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,cycloalkylcarbonyl, cycloheteroalkylcarbonyl, aralkycarbonyl,heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl,(cycloheteroalkyl)alkylcyicarbonyl, loweralkylaminocarbonyl,arylaminocarbonyl, arakylaminocarbonyl, heteroarylaminocarbonyl,heteroaralkylaminocarbonyl, cycloalkylaminocarbonyl,(cycloalkyl)alkylaminocarbonyl, cycloheteroalkylaminocarbonyl,(cycloheteroalkyl)alkylaminocarbonyl, loweralkylcarbonylamino,arylcarbonylamino, heteroarylcarbonylamino, cycloalkylcarbonylamino,cycloheteroalkylcarbonylamino, aralkcylcarbonylamino,heteroaralkylcarbonylamino, (cycloalkyl)alkylcarbonylamino,(cycloheteroalkyl)alkylcarbonylamino, loweralkylamino, arylamino,aralkylamino, heteroarylamino, heteroaralkylamino, loweralkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl,cycloheteroalkylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl,(cycloalkyl)alkylsulfonyl, (cycloheteroalkyl)alkylsulfonyl,loweralkylsulfonyl, arylsulfinyl, heteroarylsulfinyl,cycloalkylsulfinyl, cycloheteroalkylsulfinyl, aralkylsulfinyl,heteroaralkylsulfinyl, (cycloalkyl)alkylsulfinyl,(cycloheteroalkyl)alkylsulfinyl, loweralkyloxy, aryloxy, heteroaryloxy,cycloalkyloxy, cycloheteroalkyloxy, aralkyloxy, heteroaralkloxy,(cycloalkyl)alkyloxy, and (cycloheteroalkyl)alkyloxy, loweralkylthio,arylthio, heteroarylthio, cycloalkylthio, cycloheteroalkylthio,aralkylthio, heteroaralkylthio, (cycloalkyl)alkylthio,(cycloheteroalkyl)alkylthio, loweralkylthiocarbonyl, arylthiocarbonyl,heteroarylthiocarbonyl, cycloalkylthiocarbonyl,cycloheteroalkylthiocarbonyl, aralkythiocarbonyloxythiocarbonyl,heteroaralkylthiocarbonyl, (cycloalkyl)alkylthiocarbonyl,(cycloheteroalkyl)alkylthiocarbonyl, loweralkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, cycloalkyloxycarbonyl,cycloheteroalkyloxycarbonyl, aralkyoxycarbonyloxloxycarbonyl,heteroaralkyloxycarbonyl, (cycloalkyl)alkyloxycarbonyl,(cycloheteroalkyl)alkyloxycarbonyl, iminoloweralkyl, iminocycloalkyl,imninocycloheteroalkyl, iminoaralkyl, iminoheteroaralkyl,(cycloalkyl)iminoalkyl, (cycloheteroalkyl)iminoalkyl,(cycloiminoalkyl)alkyl, (cycloiminoheteroalkyl)alkyl, oximinoloweralkyl,oximinocycloalkyl, oximinocycloheteroalkyl, oximinoaralkyl,oximinoheteroaralkyl, (cycloalkyl)oximinoalkyl,(cyclooximinoalkyl)alkyl, (cyclooximinobeteroalkyl)alkyl, and(cycloheteroalkyl)oximinoalkyl. R₄ is selected from the group consistingof hydrogen, carboxyl, formyl, and optionally substituted loweralkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloheteroalkyl,loweralkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,cycloalkylcarbonyl, cycloheteroalkylcarbonyl, aralkycarbonyl,heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl,(cycloheteroalkyl)alkylcarbonyl, loweralkylaminocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl,heteroaralkylaminocarbonyl, cycloalkylaminocarbonyl,(cycloalkyl)alkylaminocarbonyl, cycloheteroalkylaminocarbonyl,(cycloheteroalkyl)alkylaminocarbonyl, loweralkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl, cycloheteroalkylsulfonyl,aralkylsulfonyl, heteroaralkysulfonyl, (cycloalkyl)alkylsulfonyl,(cycloheteroalkyl)alkylsulfonyl, loweralkylsulfinyl, arylsulfinyl,heteroarylsulfinyl, cycloalkylsulfinyl, cycloheteroalkylsulfinyl,aralkylsulfinyl, heteroaralkylsulfinyl, (cycloalkyl)alkylsulfinyl,(cycloheteroalkyl)alkylsulfinyl, arylthiocarbonyl,heteroarylthiocarbonyl, cycloalkylthiocarbonyl,cycloheteroalkylthiocarbonyl, aralkythiocarbonyloxythiocarbonyl,heteroaralkylthiocarbonyl, (cyloalkyl)alkylthiocarbonyl,(cycloheteroalkyl)alkylthiocarbonyl, loweralkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, cycloalkyloxycarbonyl,cycloheteroalkyloxycarbonyl, aralkyoxycarbonyloxloxycarbonyl,heteroaralkyloxycarbonyl, (cycloalkyl)alkyloxycarbonyl,(cycloheteroalkyl)alkyloxycarbonyl, carboxamidino,loweralkylcarboxamidino, arylcarboxamidino, aralkylcarboxamidino,heteroarylcarboxamidino, heteroaralkyl carboxamidino,cycloalkylcarboxamidino, cycloheteroalkylcarboxamindino.

[0015] In one embodiment of the invention having the generic structuresshown above, R₁ and R₃ are selected independently from the groupconsisting of optionally substituted cycloalkyl, cycloheteroalkyl,(cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl. Examples of such groupsinclude without limitation cyclohexyl, piperidinyl, adamantyl, andquinuclidyl, each optionally substituted. Other examples includecyclohexylmethyl, 2-cyclohexylethyl, and adamantylmethyl, again, eachoptionally substituted. In other embodiments, R₁ and R3 are selectedindependently from the group consisting of optionally substituted aryl,heteroaryl, aralkyl, and heteroaralkyl. More specific embodiments arethose for which R₁ and R₃ are selected independently from the groupconsisting of optionally substituted heteroaryl and heteroaralkyl, suchas pyridinyl, hydroxypyridyl, methoxypyridyl, pyridylmethyl, and thelike.

[0016] More particular embodiments are those for which R₁ and R₃ areselected independently from the group consisting of optionallysubstituted aryl and aralkyl. More particular embodiments include thosewherein at least one of R₁ and R₃ is substituted with at least onehydroxyl, alkyloxy, aryloxy, thio, alkylthio, or arylthio group. Othermore particular embodiments are those for which at least one of R₁ andR₃ is selected independently from the group consisting of phenyl,phenyloxyloweralkyl, and phenylloweralkyl and at least one of R₁ and R₃is substituted with at least one hydroxyl, alkyloxy, aryloxy, thio,alkylthio, or arylthio group.

[0017] In some embodiments of the above-illustrated compounds, R₂ isselected from the group consisting of hydrogen, halo, and optionallysubstituted loweralkyl, haloloweralkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, aryloxyalkyl, arylthioalkyl, arylcarbonyl,heteroarylcarbonyl, loweralkylcarbonyl, aminocarbonyl,arylaminocarbonyl, loweralkylaminocarbonyl, aralkylaminocarbonyl,(heterocycloloweralkyl)alkylaminocarbonyl, heteroarylaminocarbonyl,heteroaralkylaminocarbonyl, (cycloloweralkyl)aminocarbonyl, formyl, andalkenyl. More particular examples include those for which R₂ is selectedfrom the group consisting of optionally substituted phenylcarbonyl,(heterocycloalkyl)loweralkyloxyphenylcarbonyl, hydroxyphenylcarbonyl,halophenylcarbonyl, phenylloweralkylaminocarbonyl,diloweralkylaminocarbonyl, phenylloweralkylaminocarbonyl,hydroxyphenyllowerlakylaminocarbonyl, cycloalkylaminocarbonyl,loweralkylphenylcarbonyl,haloweralkylsulfonylloweralkyloxyphenylcarbonyl, andnitrophenylcarbonyl. Examples of R₂ substituents within such embodimentshaving useful properties include, but are not limited to,4-(2-piperidin-1-ylethyloxy)phenylcarbonyl, 4 -hydroxyphenylcarbonyl,(phenylmethyl)aminocarbonyl, 3-(2-oxopyrrolidin-1-yl)propylaminocarbonyl, di-n-butylaminocarbonyl,(4-hydroxyphenylrnethyl)aminocarbonyl,(pyridin-3-ylnethyl)aminocarbonyl, (pyridin-2-ylmethyl)aminocarbonyldimethylaminocarbonyl, ethylaminocarbonyl,4-(2-morpholinoethyloxy)phenylcarbonyl, 4-(3-dimethylaminopropyloxy)phenylcarbonyl, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl,4-(2-dimethylaminoethlyloxy)phenylcarbonyl,4-[2-(benzylmethylamino)ethyloxy]phenylcarbonyl, 4-(1 -methylpiperdin-3-ylmethyloxy)phenylcarbonyl,4-[2-(1-methylpyrrolidin-2-yl)ethyloxy]phenylcarbonyl,4-[2-(4-methylpiperazin-1-yl)ethyloxy]phenylcarbonyl, 4-(1-methylpiperdin-4-ylmethyloxy)phenylcarbonyl, 2-chlorophenylcarbonyl,3-chlorophenylcarbonyl, 4-chlorophenylcarbonyl, 3-nitrophenylcarbonyl,4-nitrophenylcarbonyl, 3,4-dichlorophenylcarbonyl,4-n-butylphenylcarbonyl, 3-hydroxyphenylcarbonyl,2-hydroxyphenylcarbonyl, 4-methoxyphenylcarbonyl,3-(2-piperidin-1-ylethyloxy)phenylcarbonyl,3-(2-diethylaminoethyloxy)phenylcarbonyl, 3-[2-(pyrrolidin- 1yl)ethyloxy]phenylcarbonyl,3-(1-methylpiperdin-3-ylmethyloxy)phenylcarbonyl, and3-(2-dimethylaminothyloxy)phenylcarbonyl. In another aspect, the presentinvention provides fused-ring pyrazoles having the structures:

[0018] and their pharmaceutically acceptable salts. X₅ is -X₁₀)“-,wherein n is an integer between I and 3 and X₁₀ for each value of n, isselected independently from the group consisting of oxygen, —SO_(x)—where x is and integer between 0 and 2, nitrogen, nitrogen substitutedwith optionally substituted loweralkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, arylcarbonyl, alkylcarbonyl, aralkylcarbonyl,heteroarylcarbonyl, heteroaralkylcarbonyl, and methylene or methine,each optionally substituted from the group consisting of halo, cyano,nitro, thio, amino, carboxyl, formyl, and optionally substitutedloweralkyl, loweralkylcarbonyloxy, arylcarbonyloxy,heteroarylcarbonyloxy, cycloalkylcarbonyloxy,cycloheteroalkylcarbonyloxy, aralkycarbonyloxy,heteroaralkylcarbonyloxy, (cycloalkyl)alkylcarbonyloxy,(cycloheteroalkyl)alkylcarbonyloxy, loweralkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, cycloalkylcarbonyl, cycloheteroalkylcarbonyl,aralkycarbonyl, heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl,(cycloheteroalkyl)alkylcarbonyl, loweralkylaminocarbonyl,arylaminocarbonyl, arakylaminocarbonyl, heteroarylaminocarbonyl,heteroaralkylamninocarbonyl, loweralkylcarbonylamino, arylbonylamino,heteroarylcarbonylamino, cycloalkylcarbonylamino,cycloheteroalkylcarbonylamino, arakylcarbonylamino,heteroaralkylcarbonylamino, (cycloalkyl)alkylcarbonylamino,(cycloheteroalkyl)alkylcarbonylamino, loweralkylamino, arylamino,aralkylamino, heteroarylamino, heteroaralkylamino, loweralkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl,cycloheteroalkylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl,(cycloalkyl)alkylsulfonyl, (cycloheteroalkyl)alkylsulfonyl,loweralkylsulfinyl, arylsulfinyl, heteroarylsulfonyl,cycloalkylsulfinyl, cycloheteroalkylsulfinyl, aralkylsulfinyl,heteroaralkylsulfinyl, (cycloalkyl)alkylsulfinyl,(cycloheteroalkyl)alkylsulfinyl, loweralkyloxy, aryloxy, heteroaryloxy,cycloalkyloxy, cycloheteroalkyloxy, aralkyloxy, heteroaralkyloxy,(cycloalkyl)alkyloxy, and (cycloheteroalkyl)alkyloxy, loweralkylthio,arylthio, heteroarylthio, cycloalkylthio, cycloheteroalkylthio,aralkylthio, heteroaralkylthio, (cycloalkyl)alkylthio,(cycloheteroalkyl)alkylthio, loweralkylthiocarbonyl, arylthiocarbonyl,heteroarylthiocarbonyl, cycloalkylthiocarbonyl,cycloheteroalkylthiocarbonyl, aralkythiocarbonyloxlthiocarbonyl,heteroaralkylthiocarbonyl, (cycloalkyl)alkylthiocarbonyl,(cyclobeteroalkyl)alkylthiocarbonyl, loweralkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, cycloalkyloxycarbonyl,cycloheteroalkyloxycarbonyl, aralkyoxycarbonyloxloxycarbonyl,heteroaralkyloxycarbonyl, (cycloalkyl)alkyloxycarbonyl,(cycloheteroalkyl)alkyloxycarbonyl, iminoloweralkyl, iminocycloalkyl,iminocycloheteroalkyl, iminoaralkyl, iminoheteroaralkyl,(cycloalkyl)iminoalkyl, and (cycloheteroalkyl)iminoalkyl. X₆-X₉ areselected independently from the group consisting of oxygen, sulfur,sulfinyl, nitrogen and optionally substituted methine. R₅ is selectedfrom the group consisting of hydrogen, carboxyl, formyl, and optionallysubstituted loweralkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,cycloalkyl, cycloheteroalkyl, loweralkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, cycloalkylcarbonyl, cycloheteroalkylcarbonyl,aralkycarbonyl, heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl,(cycloheteroalkyl)alkylcarbonyl, loweralkylaminocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl,heteroaralkylaminocarbonyl, cycloalkylaminocarbonyl,(cycloalkyl)alkylaminocarbonyl, cycloheteroalkylaminocarbonyl,(cycloheteroalkyl)alkylainocarbonyl, loweralkylsulfonyl, aiylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl, cycloheteroalkylsulfonyl,aralkylsulfonyl, heteroaralkylsulfonyl, (cycloalkyl)alkylsulfonyl,(cyclolieteroalkyl)alkylsulfinyl, loweralkylsulfinyl, arylsulfinyl,heteroarylsulfinyl, cycloalkylsulfinyl, cycloheteroalkylsulfinyl,aralkylsulfinyl, heteroaralkylsulfinyl, (cycloalkyl)alkylsulfinyl,(cycloheteroalkyl)alkylsulfinyl, arylthiocarbonyl,heteroarylthiocarbonyl, cycloalkylthiocarbonyl,cycloheteroalkylthiocarbonyl, aralkythiocarbonyloxythiocarbonyl,heteroaralkylthiocarbonyl, (cycloalkyl)alkylthiocarbonyl,(cycloheteroalkyl)alkylthiocarbonyl, loweralkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, cycloalkyloxycarbonyl,cycloheteroalkyloxycarbonyl, aralkyoxycarbonyloxloxycarbonyl,heteroaralkyloxycarbonyl, (cycloalkyl)alkyloxycarbonyl,(cycloheteroalkyl)alkyloxycarbonyl, carboxamidino,loweralkylcarboxyamidino, arylcarboxamidino, aralkylcarboxamidino,heteroarylcarboxamidino, heteroaralkylcarboxamidino,cycloalkylcarboxamidino, cycloheteroalkylcarboxamindino. R6 is selectedfrom the group consisting of optionally substituted loweralkyl, aryl,heteroaryl, cycloalkyl, cycloheteroalkyl, aralkyl, heteroaralkyl,(cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl. 5 ,.,.In someembodiments having the fused-ring structure shown above, n is I and X₁is selected from the group consisting of nitrogen, optionallysubstituted nitrogen, and optionally substituted methylene or methine.In other embodiments, n is 1 and X₁₀ is selected from the groupconsisting of nitrogen, optionally substituted nitrogen, and optionallysubstituted methylene or methine and RE is selected from the groupconsisting of optionally substituted aryl, heteroaryl, aralkyl, andheteroaralkyl. In other more specific embodiments, R6 includes at leastone hydroxyl, thio, or 0 optionally substituted loweralkyloxy, aryloxy,heteroaryloxy, loweralkylthio, arylthio, heteroarylthio,loweralkylcarbonyl, arylcarbonyl, or heteroarylcarbonyl moiety.

[0019] In other embodiments having the fused-ring structure shown above,n is 2 and each X₁₀ is selected independently from the group consistingof nitrogen, optionally substituted nitrogen, optionally substitutedmethylene, and optionally substituted methine. In some embodimentshaving these values for n and X₁₀, and R₆ is selected from the group 25consisting of optionally substituted aryl, heteroaryl, aralkyl, andheteroaralkyl. In other more specific embodiments, R6 includes at leastone hydroxyl, thio, or optionally substituted loweralkyloxy, aryloxy,heteroaryloxy, loweralkylthio, arylthio, heteroarylthio,loweralkylcarbonyl, arylcarbonyl, or heteroarylcarbonyl moiety.

[0020] Older embodiments include those as described above for which R5is selected from the group consisting of hydrogen and optionallysubstituted loweralkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,cycloalkyl, cycloheteroalkyl, 30 loweralkyl)nyl, arylcarbonyl,heteroarylcarbonyl, cycloalkylcarbonyl, cycloheteroalkylcarbonyl,aralkycarbonyl, heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl,(cycloheteroalkyl)alkylcarbonyl, loweralkylaminocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl,heteroaralkylaminocarbonyl, cycloalkylaminocarbonyl,(cycloalkyl)alkylaminocarbonyl, cycloheteroalkylaminocarbonyl,(cycloheteroalkyl)alkylaminocarbonyl, loweralkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl, cycloheteroalkylsulfonyl,aralkylsulfonyl, heteroaralkylsulfonyl, (cycloalkyl)alkylsulfonyl, andcycloheteroalkyl)alkylsulfonyl.

[0021] In still other embodiments having the fused-ring structure shownabove, X₆-X₉ are selected independently from the group consisting ofnitrogen and optionally substituted methine, and in more particularembodiments, at least one of X₆ -X₉ is methine substituted with a moietyselected from the group consisting of loweralkyloxy, aryloxy,heteroaryloxy, loweralkylthio, arylthio, heteroarylthio,loweralkylcarbonyl, arylcarbonyl, and heteroarylcarbonyl. In someembodiments, X₇ is methine substituted with hydroxy or loweralkyloxy.Further embodiments include the above-described characteristics ofX₆-X₉, n, R₅, and R₆ in a variety of combinations.

[0022] In yet another aspect, the present invention provides the presentinvention provides methods for treating or preventing an estrogenreceptor-mediated disorder in a human or animal subject in which anamount of an estrogen receptor-modulating compound of the invention thatis effective to modulate estrogen receptor activity in the subject.Other embodiments provided methods for treating a cell or a estrogenreceptor-mediated disorder in a human or animal subject, comprisingadministering to the cell or to the human or animal subject an amount ofa compound or composition of the invention effective to modulateestrogen receptor activity in the cell or subject. Representativeestrogen receptor-mediated disorders include, for example, osteoporosis,atherosclerosis, estrogen-mediated cancers breast and endometrialcancer), and Alzheimer's disease.

[0023] These and other aspects and advantages will become apparent whenthe Description below is read in conjunction with the accompanyingExamples.

4. Description of some Embodiments of the Invention

[0024] 4.1 Definitions

[0025] 4.1.1 Estrogen Receptor “Estrogen Receptor” as defined hereinrefers to any protein in the nuclear receptor gene family that bindsestrogen, including, but not limited to, any isoforms or deletionmutations having the characteristics just described. More particularly,the present invention relates to estrogen receptor(s) for human andnon-human mammals (e.g., animals of veterinary interest such as horses,cows, sheep, and pigs, as well as household pets such as cats and dogs).Human estrogen receptors included in the present invention include theα- and β- isoforms (referred to herein as “ERα“ and “ERβ”) in additionto any additional isoforms as recognized by those of skill in thebiochemistry arts.

[0026] 4.1.2 Estrogen Receptor Modulator “Estrogen Receptor Modulator”refer herein to a compound that can act as an estrogen receptor agonistor antagonist of estrogen receptor having an IC₅₀ or EC₅₀ with respectto ERα and/or ERβ of no more than about 10 μM as determined using theERα and/or ERβ transactivation assay described hereinbelow (Section5.2.2.3). More typically, estrogen receptor modulators of the inventionhave IC₅₀ of EC₅₀ values (as agonists or antagonists) of not more thanabout 5 μM. Representative compounds of the present invention have beendiscovered to exhibit agonist or antagonist activity viz. estrogenreceptor. Compounds of the present invention preferably exhibit anantagonist or agonist IC₅₀ or EC₅₀ with respect to ERαand/or ERβof nomore than about 5 μM, more preferably, no more than about 500 nM, evenmore preferably not more than about 1 NMR, and most preferably, not morethan about 500 nM, as measured in the ERα and/or ERβ transactivationassays.“IC_(50 ” is that concentration of compound which reduces the activity of a target (e.g., ERα)orERβto half-maximal level. “EC₅₀” is that concentration of compound whichprovides half- maximum effect.

[0027] 4.1.3 Selective Estrogen Receptor Modulator

[0028] A “Selective Estrogen Receptor Modulator”(or “SERM”) is acompound that exhibits activity as an agonist or antagonist of anestrogen receptor (e.g., ERαor ERβ ) in a tissue-dependent manner. Thus,as will be apparent to those of skill in the biochemistry andendocrinology arts, compounds of the invention that function as SERMscan act as estrogen receptor agonists in some tissues (e.g., bone,brain, and/or heart) and as antagonists in other tissue types, such asthe breast and/or uterine lining.

[0029] 4.1.4 Optionally substituted

[0030] “Optionally substituted” refers to the replacement of hydrogenwith a monovalent or divalent radical. Suitable substitution groupsinclude, for example, hydroxyl, nitro, amino, imino, cyano, halo, thio,thioamido, anidino, oxo, oxamidino, methoxamidino, imidino, guanidino,sulfonamido, carboxyl, formyl, loweralkyl, haloloweralkyl, loweralkoxy,haloloweralkoxy, loweralkoxyalkyl, alkylcarbonyl, arylcarbonyl,aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio,aminoalkyl, cyanoalkyl, and the like. The substitution group can itselfbe substituted. The group substituted onto the substitution group canbe, for example, carboxyl, halo; nitro, amino, cyano, hydroxyl,loweralkyl, loweralkoxy, aminocarbonyl, —SR, thioamido, —SO₃H, —S0₂R orcycloalkyl, where R is typically hydrogen, hydroxyl or loweralkyl. Whenthe substituted substituent includes a straight chain group, thesubstitution can occur either within the chain (eg., 2-hydroxypropyl,2-aminobutyl, and the like) or at the chain terminus (e.g,2-hydroxyethyl, 3-cyanopropyl, and the like). Substituted substituentscan be straight chain, branched or cyclic arrangements of covalentlybonded carbon or heteroatoms.

[0031] 4.1.5 Loweralkyl and Related Terms

[0032] “Loweralkyl” as used herein refers to branched or straight chainalkyl groups comprising one to ten carbon atoms that independently areunsubstituted or substituted, e.g., with one or more halogen, hydroxylor other groups. Examples of loweralkyl groups include, but are notlimited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, n-hexyl,neopentyl, trifluoromethyl, pentafluoroethyl, and the like.

[0033] “Alkylenyl” refers to a divalent straight chain or branched chainsaturated aliphatic radical having from 1 to 20 carbon atoms. Typicalalkylenyl groups employed in compounds of the present invention areloweralkylenyl groups that have from 1 to about 6 carbon atoms in theirbackbone. “Alkenyl” refers herein to straight chain, branched, or cyclicradicals having one or more double bonds and from 2 to 20 carbon atoms.“Alkenyl” refers herein to straight chain, branched, or cyclic radicalshaving one or more triple bonds and from 2 to 20 carbon atoms.

[0034] The term “haloloweralkyl” refers to a loweralkyl radicalsubstituted with one or more halogen atoms. groups include medioxy,ethoxy, t-butoxy, trifluoromethoxy and the like.

[0035] “Loweralkythio“ as used herein refers to RS—wherein R isloweralkyl.

[0036] The term “alkoxyalkyl” refers to the group -alk₁-O-alk₂ wherealk₁, is alkylenyl or alkenyl, and alk₂ is alkyl or alkenyl. The term“loweralkoxyalkyl” refers to an alkoxyalkyl where alk₁, isloweralkylenyl or loweralkenyl, and alk₂ is loweralkyl or loweralkenyl.The term “aryloxyalkyl” refers to the group -alkylenyl-0-alyl. The term“aralkoxyalkyl“refers to the group -alkylenyl-O-aralkyl, where aralkylis a loweraralkyl.

[0037] “Cycloalkyl” refers to a mono- or polycyclic, loweralkylsubstituent. Typical cycloalkyl substituents have from 3 to 8 backbone(i e., ring) atoms in which each backbone atom is optionally substitutedcarbon. When used in context with cycloalkyl substituents, the term“polycyclic” refers herein to fused, non-fused cyclic carbon structuresand spirocycles. Examples of cycloalkyl groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl,bornyl, norbomyl, and the like.

[0038] The term “cycloheteroalkyl” refers herein to cycloalkylsubstituents that have from 1 to 5, and more typically from 1 to 4heteroatoms (ie., non-carbon atoms such as nitrogen, sulfur, and oxygen)in the ring structure, with the balance of atoms in the ring beingoptionally substituted carbon. Representative heterocycloalkyl moietiesinclude, for example, morpholino, piperazinyl, piperidinyl,pyrrolidinyl, methylpryolidinyl, pyrrolidinone-yl, and the like.

[0039] The terms “(cycloalkyl)alkyl” and “(cycloheteroalkyl)alkyl” referto alkyl chains substituted with cycloalkyl and cyclolheteroalkyl groupsrespectively.

[0040] The term “haloalkoxy” refers to an alkoxy radical substitutedwith one or more halogen atoms. The term “haloloweralkoxy” refers to aloweralkoxy radical substituted with one or more halogen atoms.

[0041] 4.1.6 Halo

[0042] “Halo“ refers herein to a halogen radical, such as fluorine,chlorine, bromine, or iodine.

[0043] 4.1.7 Aryl and Related Terms

[0044] “Aryl” refers to monocyclic and polycyclic aromatic groups, orfused ring systems having at least one aromatic ring, having from 3 to14 backbone carbon atoms. Examples of aryl groups include withoutlimitation phenyl, naphthyl, dihydrotiaphtyl, tetrahydronaphthyl, andthe like.

[0045] “Aralkyl” refers to a alkyl group substituted with an aryl group.Typically, aralkyl groups employed in compounds of the present inventionWave from I to 6 carbon atoms incorporated within the alkyl portion ofthe aralkyl group. Suitable aralkyl groups employed in compounds of thepresent invention include, for example, benzyl, picolyl, and the like.

[0046] 4.1.8 Heteroaryl and Related Terms

[0047] The term “heteroaryl” refers herein to aryl groups having fromone to four heteroatoms as ring atoms in an aromatic ring with theremainder of the ring atoms being aromatic or non-aromatic carbon atoms.When used in connection with aryl substituents, the term “polycyclic”refers herein to fused and non-fused cyclic structures in which at leastone cyclic structure is aromatic, such as, for example, benzodioxozolo,naphthyl, and the like. Exemplary heteroaryl moieties employed assubstituents in compounds of the present invention include pyridyl,pyrimidinyl, thiazolyl, indolyl, imidazolyl, oxadiazolyl, tetrazolyl,pyrazinyl, triazolyl, thiophenyl, furanyl, quinolinyl, purinyl,benzothiazolyl, benzopyridyl, and benzimidazolyl, and the like.

[0048] 4.1.9 Amino and Related Terms “Amino” refers herein to the group—NH₂. The term “loweralkylamino” refers herein to the group —NRR′ whereR and R′ are each independently selected from hydrogen or loweralkyl.The term “arylamino” refers herein to the group —NRR′ where R is arylarid R′ is hydrogen, loweralkyl, aryl, or aralkyl. The term“aralkylamino” refers herein to the group —NRR′ where R is aralkyl andR′ is hydrogen, loweralkyl, aryl, or aralkyl. The terms“heteroarylamino” and heteroalkylamino” are defined by analogy toarylamino and aralkylamino.

[0049] The term “aminocarbonyl” refers herein to the group —C(O)—NH₂.The terms “loweralkylaminocarbonyl”, arylaminocarbonyl”,“aralkylaminocarbonyl”, “heteroarylaminocarbonyl”, and“heteroaralkylaminocarbonyl” refer to —C(O)NRR′where R andR′independently are hydrogen and optionally substituted loweralkyl,aryl, aralkyl, heteroaryl, and heteroaralkyl respectively by analogy tothe corresponding terms above.

[0050] 4.1.10 Thio, Sulfonyl, Sulfinyl and Related Terms

[0051] The term “thio” refers to —SH. The terms “loweralkylthio”,“arylthio”, “heteroarylthio”, “cycloalkylthio”, “cycloheteroalkyl ”,“aralkylthio”, “heteroaralkylthio”, “(cycloalkyl)alkylthio”, and“(cycloheteroalkyl)alkylthio”refer to —SR, where R is optionallysubstituted loweralkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl,aralkyl, heteroaralkyl, (cycloalkyl)alkyl, and (cycloheteroalkyl)alkylrespectively.

[0052] The term “sulfonyl” refers herein to the group —SO₂—. The terms“loweralkylsulfonyl”, “arylsulfonyl”, “heteroarylsulfonyl”,“cycloalkylsulfonyl”, “cycloheteroalkylsulfonyl”, “aralkylsulfonyl”,“heteroaralkylsulfonyl”, “(cycloalkyl)alkylsulfonyl”, and“(cycloheteroalkyl)alkylsulfonyl” refer to —SO₂R where R is optionallysubstituted loweralkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl,aralkyl, heteroaralkyl, (cycloalkyl)alkyl, and (cycloheteroalkyl)alkylrespectively.

[0053] The term “sulfinyl” refers herein to the group —SO—. The terms“loweralkylsulfinyl”, “arylsulfinyl”, “heteroarylsulfinyl”,“cycloalkylsulfinyl”, “cycloheteroalkylsulfinyl”, “aralkylsulfinyl”,“heteroaralkylsulfinyl”, “(cycloalkyl)alkylsulfinyl”, and“(cycloheteroalkyl)alkylsulfinyl”refer to —SOR where R is optionallysubstituted loweralkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl,aralkyl, heteroaralkyl, (cycloalkyl)alkyl, and (cycloheteroalkyl)alkylrespectively.

[0054] 4.1.11 Formyl, Carboxyl, Carbonyl, Thiocarbonyl, and RelatedTerms

[0055] “Formyl” refers to —C(O)H.

[0056] “Carboxyl” refers to —C(O)OH.

[0057] “Carbonyl” refers to the divalent group —C(O)—. The terms“loweralkylcarbonyl”, “arylcarbonyl”, “heteroarylcarbonyl”,“cycloalkylcarbonyl”, “cycloheteroalkylcarbonyl”, “aralkycarbonyl”,“heteroaralkylcarbonyl”, “(cycloalkyl)alkylcarbonyl”, and“(cycloheteroalkyl)alkylcarbonyl” refer to —C(O)R, where R is optionallysubstituted loweralkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl,aralkyl, heteroaralkyl, (cycloalkyl)alkyl, and (cycloheteroalkyl)alkylrespectively.

[0058] “Thiocarbonyl” refers to the group —C(S)—. The terms“loweralkylthiocarbonyl”, “arylthiocarbonyl”, “heteroarylthiocarbonyl”,“cycloalkylthiocarbonyl”, “cycloheteroalkylthiocarbonyl”,“aralkythiocarbonyloxithiocarbonyl”, “heteroaralkylthiocarbonyl”,“(cycloalkyl)alkylthiocarbonyl”, and“(cycloheteroalkyl)alkylthiocarbonyl” refer to —C(S)R, where R isoptionally substituted loweralkyl, aryl, heteroaryl, cycloalkyl,cycloheteroalkyl, aralkyl, heteroaralkyl, (cycloalkyl)alkyl, and(cycloheteroalkyl)alkyl respectively.

[0059] “Carbonyloxy“ refers generally to the group —C(O)—O—. The terms“loweralkylcarbonyloxy”, “arylcarbonyloxy”, “heteroarylcarbonyloxy”,“cycloalkylcarbonyloxy”, “cycloheteroalkylcarbonyloxy”,“aralkycarbonyloxy”, “heteroalkylcarbonyloxy”,“(cycloalkyl)alkylcarbonyloxy”, “(cycloheteroalkyl)alkylcarbonyloxy”refer to —C(O)OR, where R is optionally substituted loweralkyl, aryl,heteroaryl, cycloalkyl, cycloheteroalkyl, aralkyl, heteroaralkyl,(cycloalkyl)alkyl and (cycloheteroalkyl)alkyl respectively.“Oxycarbonyl” refers to the group —O—C(O)—. The terms“loweralkyloxycarbonyl”, “aryloxycarbonyl”, “heteroaryloxycarbonyl”,“cycloalkyloxycarbonyl”, “cycloheteroalkyloxycarbonyl”,“aralkyoxycarbonyloxycarbonyl”, “heteroaralkyloxycarbonyl”,“(cycloalkyl)alkyloxycarbonyl”, “(cycloheteroalkyl)alkyloxycarbonyl”refer to —O—C(O)R, where R is optionally substituted loweralkyl, aryl,heteroaryl, cycloalkyl, cycloheteroalkyl, aralkyl, heteroaralkyl,(cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl respectively.

[0060] “Carbonylamino” refers to the group —NH—C(O)—. The terms“loweralkylcarbonylamino”, “arylcarbonylamino”, “heteroarylcarbonyl”,“cycloalkylcarbonylamino”, “cycloheteroalkylcarbonylamino”,“aralkcylcarbonylamino“, “heteroalkylcarbonylamino”,“(cycloalkyl)alkylcarbonylamino”, and“(cycloheteroalkyl)alylcarbonylamino” refer to —NH—C(O)R, where R isoptionally substituted loweralkyl, aryl, heteroaryl, cycloalkyl,cycloheteroalkyl, aralkyl, heteroaralkyl, (cycloalkyl)alkyl, or(cycloheteroalkyl)alkyl respectively. In addition, the present inventionincludes N-substituted carbonylamino′(—NR′C(O)R), where R′is optionallysubstituted loweralkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl andR retains the previous definition.

[0061] 4.4.12 Guanidino or Guanidyl

[0062] As used herein, the term “guanidino” or “guanidyl” refers tomoieties derived from guanidine, H₂N—C(═NH)—NH₂. Such moieties includethose bonded at the nitrogen atom carrying the formal double bond (the“2”-position of the guanidine, e.g., diaminomethyleneamino, (H₂N)₂C═NH—)and those bonded at either of the nitrogen atoms carrying a formalsingle bond (the “1-” and/or “3”-positions of the guanidine, e.g.,H₂N—C(═NH)—NH—). The hydrogen atoms at either nitrogen can be replacedwith a suitable substituent, such as loweralkyl, aryl, or loweraralkyl.

[0063] 4.1.13 Amidino

[0064] As used herein, the term “amidino” refers to the moietiesR—C(═N)—NR′—(the radical being at the “N¹” nitrogen) and R(NR′)C═N— (theradical being at the “N²” nitrogen), where R and R′can be hydrogen,loweralkyl, aryl, or loweraralkyl.

[0065] 4.1.14 Imino and Oximino

[0066] The term “imino” refers to the group —C(═NR)—, where R can behydrogen or optionally substituted loweralkyl, aryl, heteroaryl, orheteroaralkyl respectively. The terms “iminoloweralkyl”,“iminocycloalkyl”, “iminocycloheteroalkyl”, “iminoaralkyl”,“iminoheteroaralkyl”, “(cycloalkyl)iminoalkyl”,“(cycloiminoalkyl)alkyl“, “(cycloiminoheteroalkyl)alkyl”, and“(cycloheteroalkyl)iminoalkyl” refer to optionally substitutedloweralkyl, cycloalkyl, cycloheteroalkyl, aralkyl, heteroaralkyl,(cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl groups that include animino group, respectively.

[0067] The term “oximino” refers to the group —C(═NOR)—, where R can behydrogen (“hydroximino”) or optionally substituted loweralkyl, aryl,heteroaryl, or heteroaralkyl respectively. The terms“oximinoloweralkyl”, “oximinocycloalkyl”, “oximinocycloheteroalkyl”,“oximinoaralkyl”, “oximinoheteroaralkyl”, “(cycloalkyl)oximinoalkyl”,“(cyclooximinoalkyl)alkyl”, “(cyclooximinoheteroalkyl)alkyl”, and(cycloheteroalkyl)oximinoalkyl” refer to optionally substitutedloweralkyl, cycloalkyl, cycloheteroalkyl, aralkyl, heteroaralkyl,(cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl groups that include anoximino group, respectively.

[0068] 4.1.15 Methylene and Methine

[0069] The term “methylene” as used herein refers to an unsubstituted,monosubstituted, or disubstituted carbon atom having a formal sp³hybridization (i.e., —CRR′—, where R and R′ are hydrogen or independentsubstituents).

[0070] The term “methine” as used herein refers to an unsubstituted orcarbon atom having a formal sp² hybridization (i.e., —CR═ or ═CR—, whereR is hydrogen a substituent).

[0071] 4.2 Compounds of the Invention

[0072] The present invention provides compounds that have useful agonistand/or antagonist activity with respect to mammalian estrogen receptorsin addition to compounds, compositions, and methods useful for treatingestrogen receptor-mediated disorders in mammals. More particularly, thecompounds of the present invention have been found to possess asurprising degree of activity with respect to the α- and β-isoforms ofhuman estrogen receptor. Thus, the compounds, compositions, and methodsdescribed herein have utility in preventing and/or treating a widevariety of estrogen receptor-mediated disorders including, but notlimited to, osteoporosis, breast cancer, uterine cancer, and congestiveheart disease.

[0073] In a first aspect, the present invention provides compoundshaving the structures:

[0074] and their pharmaceutically acceptable salts. R₁ and R₃ areselected independently from the group consisting of optionallysubstituted loweralkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl,aralkyl, heteroaralkyl, (cycloalkyl)alkyl. R₂ is selected from the groupconsisting of hydrogen, halo, cyano, nitro, thio, amino, carboxyl,formyl, and optionally substituted loweralkyl, loweralkylcarbonyloxy,arylcarbonyloxy, heteroarylcarbonyloxy, cycloalkylcarbonyloxy,cycloheteroalkylcarbonyloxy, aralkycarbonyloxy,heteroaralkylcarbonyloxy, (cycloalkyl)alkylcarbonyloxy,(cycloheteroalkyl)alkylcarbonyloxy, loweralkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, cycloalkylcarbonyl, cycloheteroalkylcarbonyl,aralkycarbonyl, heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl,(cycloheteroalkyl)alkylcarbonyl, loweralkylaminocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl,heteroaralkylaminocarbonyl, cycloalkylaminocarbonyl,(cycloalkyl)alkylaminocarbonyl, cycloheteroalkylaminocarbonyl,(cycloheteroalkyl)alkylaminocarbonyl, loweralkylcarbonylamino,arylcarbonylamino, heteroarylcarbonylamino, cycloalkylcarbonylamino,cycloheteroalkylcarbonylamino, aralkylcarbonylamino,heteroaralkylcarbonylamino, (cycloalkyl)alkylcarbonylamino,(cycloheteroalkyl)alkylcarbonylamino, loweralkylamino, arylamino,aralkylamino, heteroarylamino, heteroaralkylamino, loweralkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl,cycloheteroalkylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl,(cycloalkyl)alkylsulfonyl, (cycloheteroalkyl)alkylsulfonyl,loweralkylsulfinyl, arylsulfinyl, heteroarylsulfinyl,cycloalkylsulfinyl, cycloheteroalkylsulfinyl, arylsulfinyl,heteroaralkylsulfinyl, (cycloalkyl)alkylsulfinyl,(cycloheteroalkyl)alkylsulfinyl, loweralkyloxy, aryloxy, heteroaryloxy,cycloalkyloxy, cycloheteroalkyloxy, aralkyloxy, heteroaralkyloxy,(cycloalkyl)alkyloxy, and (cycloheteroalkyl)alkyloxy, loweralkylthio,arylthio, heteroarylthio, cycloalkylthio, cycloheteroalkylthio,aralkylthio, heteroaralkylthio, (cycloalkyl)alkylthio,(cycloheteroalkyl)alkylthio, loweralkylthiocarbonyl, arylthiocarbonyl,heteroarylthiocarbonyl, cycloalkylthiocarbonyl,cycloheteroalkylthiocarbonyl, aralkythiocarbonyloxythiocarbonyl,heteroaralkylthiocarbonyl, (cycloalkyl)alkylthiocarbonyl,(cycloheteroalkyl)alkylthiocarbonyl, loweralkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, cycloalkyloxycarbonyl,cycloheteroalkyloxycarbonyl, aralkyoxycarbonyloxloxycarbonyl,heteroaralkyloxycarbonyl, (cycloalkyl)alkyloxycarbonyl,(cycloheteroalkyl)alkyloxycarbonyl, iminoloweralkyl, iminocycloalkyl,iminocycloheteroalkyl, iminoaralkyl, iminoheteroaralkyl,(cycloalkyl)iminoalkyl, (cycloheteroalkyl)iminoalkyl,(cycloiminoalkyl)alkyl, (cycloiminoheteroalkyl)alkyl, oximinoloweralkyl,oximinocycloalkyl, oximinocycloheteroalkyl, oximinoaralkyl,oximinoheteroaralkyl, (cycloalkyl)oximinoalkyl,(cyclooximinoalkyl)alkyl, (cyclooximinoheteroalkyl)alkyl, and(cycloheteroalkyl)oximinoalkyl. R₄ is selected from the group consistingof hydrogen, carboxyl, formyl, and optionally substituted loweralkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloheteroalkyl,loweralkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,cycloalkylcarbonyl, cycloheteroalkylcarbonyl, aralkycarbonyl,heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl,(cycloheteroalkyl)alkylcarbonyl, loweralkylaminocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl,heteroaralkylaminocarbonyl, cycloalkylaminocarbonyl,(cycloalkyl)alkylaminocarbonyl, cycloheteroalkylaminocarbonyl,(cycloheteroalkyl)alkylaminocarbonyl, loweralkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl, cycloheteroalkylsulfonyl,aralkylsulfonyl, heteroaralkylsulfonyl, (cycloalkyl)alkylsulfonyl,(cycloheteroalkyl)alkylsulfonyl, loweralkylsulfinyl, arylsulfinyl,heteroarylsulfinyl, cycloalkylsulfinyl, cycloheteroalkylsulfinyl,aralkylsulfinyl, heteroaralkylsulfinyl, (cycloalkyl)alkylsulfinyl,(cycloheteroalkyl)alkylsulfinyl, arylthiocarbonyl,heteroarylthiocarbonyl, cycloalkylthiocarbonyl,cycloheteroalkylthiocarbonyl, aralkythiocarbonyloxythiocarbonyl,heteroaralkylthiocarbonyl, (cycloalkyl)alkylthiocarbonyl,(cycloheteroalkyl)alkylthiocarbonyl, loweralkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, cycloalkyloxycarbonyl,cycloheteroalkyloxycarbonyl, aralkyoxycarbonyloxloxycarbonyl,heteroaralkyloxycarbonyl, (cycloalkyl)alkyloxycarbonyl,(cycloheteroalkyl)alkyloxycarbonyl, carboxamidino,loweralkylcarboxamidino, arylcarboxamidino, aralkylcarboxamidino,heteroarylcarboxamidino, heteroaralkylcarboxamidino,cycloalkylcarboxamidino, cycloheteroalkylcarboxamindino.

[0075] In one embodiment of the invention having the generic structuresshown above, R₁ and R₃ are selected independently from the groupconsisting of optionally substituted cycloalkyl, cycloheteroalkyl,(cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl. Examples of such groupsinclude without limitation cyclohexyl, piperidinyl, adamantyl, andquinuclidyl, each optionally substituted. Other examples includecyclohexylmethyl, 2-cyclohexylethyl, and adamantylmethyl, again, eachoptionally substituted. In other embodiments, R₁ and R₃ are selectedindependently from the group consisting of optionally substituted aryl,heteroaryl, aralkyl, and heteroaralkyl. More specific embodiments arethose for which R₁ and R₃ are selected independently from the groupconsisting of optionally substituted heteroaryl and heteroaralkyl, suchas pyridinyl, hydroxypyridyl, methoxypyridyl, pyridylmethyl, and thelike.

[0076] In another embodiment, R₁ and R₃ are selected independently fromthe group consisting of optionally substituted aryl and aralkyl. In someembodiments in which R₁ and R₃ are selected independently from the groupconsisting of optionally substituted aryl and aralkyl, at least one ofR₁ and R₃ is substituted with at least one hydroxyl, alkyloxy, aryloxy,thio, alkylthio, or arylthio group. More specific embodiments are thosewherein R₁ and R₃ are selected independently from the group consistingof optionally substituted aryl and aralkyl, at least one of R₁ and R₃ issubstituted with at least one hydroxyl, alkyloxy, aryloxy, thio,alkylthio, or arylthio group, and at least one of R₁ and R₃ is selectedindependently from the group consisting of phenyl, phenyloxyloweralkyl,and phenylloweralkyl. In still more specific embodiments, at least oneof R₁ and R₃ is selected independently from the group consisting ofphenyl, phenyloxyloweralkyl, and phenylloweralkyl as just described andat least one of R₁ and R₃ is substituted optionally with a substituentselected from the group consisting of halogen, nitro, cyano, loweralkyl,haloloweralkyl, loweralkyloxy, haloloweralkyloxy, carboxy,loweralkyloxycarbonyl, aryloxycarbonyl, (cycloloweralkyl)oxycarbonyl,aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl,(heterocycloloweralkyl)oxycarbonyl, loweralkylsulfinyl,loweralkylsulfonyl, loweralkylthio, arylthio, loweralkylcarbonyloxy,arylcarbonyloxy, arakylcarbonyloxy, heteroarylcarbonyloxy,heteroaralkylcarbonyloxy, (cycloloweralkyl)carbonyloxy,alkylsulfonylamino, (heterocycloloweralkyl)carbonyloxy, aminocarbonyl,loweraklylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl,heteroarylaminocarbonyl, and heteroaralkylaminocarbonyl. In furtherembodiments in which at least one of R₁ and R₃ is selected independentlyfrom the group consisting of phenyl, phenyloxyloweralkyl, andphenylloweralkyl as just described, at least one of R₁ and R₃ issubstituted optionally with a substituent selected from the groupconsisting of halogen, nitro, cyano, loweralkyl, halolowerlalkyl,loweralkyloxy, halolowerlakyloxy, carboxy, loweralkylthio,aminocarbonyl, and loweralkylsulfinyl.

[0077] In other embodiments of the above-illustrated pyrazolederivatives of the invention, R₂ is selected from the group consistingof hydrogen, halo, and optionally substituted loweralkyl,haloloweralkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxyalkyl,arylthioalkyl, arylcarbonyl, heteroarylcarbonyl, loweralkylcarbonyl,aminocarbonyl, arylaminocarbonyl, loweralkylaminocarbonyl,aralkylaminocarbonyl, (heterocycloloweralkyl)alkylaminocarbonyl,heteroarylaminocarbonyl, heteroaralkylaminocarbonyl,(cycloloweralkyl)aminocarbonyl, formyl, and alkenyl. In some morespecific embodiments, R₂ is selected from the group consisting ofhydrogen and halo. In other more specific embodiments, R₂ is selectedfrom the group consisting of optionally substituted phenyl,phenylloweralkyl, hydroxyphenyl, loweralkyloxyphenyl,haloloweralkylsulfonylloweralkyloxyphenyl,diloweralkylaminoloweralkyloxyphenyl,(cycloaminoloweralkyl)loweralkyloxyphenyl, andheterocycloalkyl)loweralkyloxyphenyl. Examples of specific useful groupsof this embodiment include without limitation 2-methyl-4-hydroxyphenyl,2-aminocarbonyl-4-hydroxyphenyl, 4-methylsulfonylaminophenyl,3-aminocarbonyl- 4-hydroxyphenyl, 3-aminocarbonyl-4-methoxyphenyl,3-chloro-4-hydroxyphenyl, 4-methylcarbonyloxyphenyl,3-n-hexyl-4-hydroxyphenyl, 4-n-propylcarbonyloxyphenyl,3-ethyl-4-hydroxyphenyl, 2-methylsulfinyl-4-hydroxyphenyl,2-ethyl-4-hydroxyphenyl, 2-carboxy-4-hydroxyphenyl,3-fluoro-4-hydroxyphenyl, 2-iodo-4-hydroxyphenyl,2-n-butyl-4-hydroxyphenyl, 2-trifluoromethoxyphenyl, 4-methoxyphenyl,2-hydroxyphenyl, 3-phenylthio)-4-hydroxyphenyl, and3-methylphenyl-4-hydroxyphenyl, and 4-fluorophenyl. Still otherembodiments include those for which R₂ is selected from the groupconsisting of optionally substituted loweralkyl, haloloweralkyl,hydroxyalkyl, phenyloxyloweralkyl, hydroxyphenyloweralkyl,haloloweralkylsulfonylloweralkyl, and phenylthioloweralkyl. Examples ofuseful groups include without limitation 4-hydroxyphenyl, phenylmethyl,4-hydroxyphenylmethyl, 3-hydroxyphenylmethyl,2-thio-4-hydroxyphenylmethyl, 2-(4-hydroxyphenyl)ethyl,phenyloxy)methyl.

[0078] Still more specific embodiments have the latter substituentpattern and R₂ is selected from the group consisting of optionallysubstituted phenylcarbonyl,(heterocycloalkyl)loweralkyloxyphenylcarbonyl, hydroxyphenylcarbonyl,halophenylcarbonyl, phenylloweralkylaminocarbonyl,diloweralkylaminocarbonyl, phenylloweralkylaminocarbonyl,hydroxyphenyllowerlakylaminocarbonyl, cycloalkylaminocarbonyl,loweralkylphenylcarbonyl,haloloweralkylsulfonylloweralkyloxyphenylcarbonyl, andnitrophenylcarbonyl. Examples of R₂ substituents within this embodimenthaving useful properties include, but are not limited to,4-(2-piperidin-1-ylethyloxy)phenylcarbonyl, 4-hydroxyphenylcarbonyl,(phenylmethyl)aminocarbonyl,3-(2-oxopyrrolidin-1-yl)propylaminocarbonyl, di-n-butylaminocarbonyl,(4-hydroxyphenylmethyl)aminocarbonyl, (pyridin-3-ylmethyl)aminocarbonyl,(pyridin-2-ylmethyl)aminocarbonyl, dimethylaminocarbonyl,ethylaminocarbonyl, 4-(2-morpholinoethyloxy)phenylcarbonyl,4-(3-dimethylaminopropyloxy)phenylcarbonyl, cyclopropylaminocarbonyl,cyclobutylaminocarbonyl, 4-(2-dimethylaminoethyloxy)phenylcarbonyl,4-[2-(benzylmethylamino)ethyloxy]phenylcarbonyl,4-(1-methylpiperdin-3-ylmethyloxy)phenylcarbonyl,4-[2-(1-methylpyrrolidin-2-yl)ethyloxy]phenylcarbonyl,4-[2-(4-methylpiperazin-1-yl)ethyloxy[phenylcarbonyl,4-(1-methylpiperdin-4-ylmethyloxy)phenylcarbonyl,2-chlorophenylcarbonyl, 3-chlorophenylcarbonyl, 4-chlorophenylcarbonyl,3-nitrophenylcarbonyl, 4-nitrophenylcarbonyl,3,4-dichlorophenylcarbonyl, 4-n-butylphenylcarbonyl,3-hydroxyphenylcarbonyl, 2-hydroxyphenylcarbonyl,4-methoxyphenylcarbonyl-3-(2-piperidin-1-ylethyloxy)phenylcarbonyl,3-(2-diethylaminoethyloxy)phenylcarbonyl,3-[2-(pyrrolidin-1-yl)ethyloxy]phenylcarbonyl,3-(1-methylpiperdin-3-ylmethyloxy)phenylcarbonyl, and3-(2-dimethylaminoethyloxy)phenylcarbonyl.

[0079] In some embodiments for which R₂ is selected from the groupconsisting of optionally substituted phenylcarbonyl,heterocycloalkyl)loweralkyloxyphenylcarbonyl, hydroxyphenylcarbonyl,halophenylcarbonyl, phenylloweralkylaminocarbonyl,diloweralkylaminocarbonyl, phenylloweralkylaminocarbonyl,hydroxyphenyllowerlakylaminocarbonyl, cycloalkylaminocarbonyl,loweralkylphenylcarbonyl,haloloweralkylsulfonylloweralkyloxyphenylcarbonyl, andnitrophenylcarbonyl as just described, R₁ and R₃ are selectedindependently from the group consisting of optionally substitutedcycloalkyl, cycloheteroalkyl, (cycloalkyl)alkyl, and(cycloheteroalkyl)alkyl. More specific embodiments of these compoundsinclude those for which R₁ and R₃ are selected independently from thegroup consisting of optionally substituted aryl, heteroaryl, aralkyl,and heteroaralkyl. Other more specific embodiments of compounds forwhich R₂ is selected from the group consisting of optionally substitutedphenylcarbonyl, (heterocycloalkyl)loweralkyloxyphenylcarbonyl,hydroxyphenylcarbonyl, halophenylcarbonyl,phenylloweralkylaminocarbonyl, diloweralkylaminocarbonyl,phenylloweralkylaminocarbonyl, hydroxyphenyllowerlakylaminocarbonyl,cycloalkylaminocarbonyl, loweralkylphenylcarbonyl,haloloweralkylsulfonylloweralkyloxyphenylcarbonyl, andnitrophenylcarbonyl and R₁ and R₃ are selected independently from thegroup consisting of optionally substituted cycloalkyl, cycloheteroalkyl,(cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl include those wherein R₁and R₃ are selected independently from the group consisting ofoptionally substituted aryl and aralkyl. In other embodiments of thislatter substitution pattern, at least one of R₁ and R₃ is substitutedwith at least one hydroxyl or thio group. Still more detailedembodiments for which R₂ is selected from the group consisting ofoptionally substituted phenylcarbonyl,(heterocycloalkyl)loweralkyloxyphenylcarbonyl, hydroxyphenylcarbonyl,halophenylcarbonyl, phenylloweralkylaminocarbonyl,diloweralkylaminocarbonyl, phenylloweralkylaminocarbonyl,hydroxyphenyllowerlakylaminocarbonyl, cycloalkylaminocarbonyl,loweralkylphenylcarbonyl,haloloweralkylsulfonylloweralkyloxyphenylcarbonyl, andnitrophenylcarbonyl and R₁ and R₃ are selected independently from thegroup consisting of optionally substituted cycloalkyl, cycloheteroalkyl,cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl include those wherein R₁and R₃ are selected independently from the group consisting ofoptionally substituted aryl and aralkyl. In other embodiments of thislatter substitution pattern, at least one of R₁ and R₃ is substitutedwith at least one hydroxyl or thio group include those wherein at leastone of R₁ and R₃ is selected independently from the group consisting ofphenyl, phenyloxyloweralkyl, and phenylloweralkyl.

[0080] Still more detailed embodiments of the above-illustratedpyrazoles of the invention are those for which R₂ is selected from thegroup consisting of optionally substituted phenylcarbonyl,heterocycloalkyl)loweralkyloxyphenylcarbonyl, hydroxyphenylcarbonyl,halophenylcarbonyl, phenylloweralkylaminocarbonyl,diloweralkylaminocarbonyl, phenylloweralkylaminocarbonyl,hydroxyphenyllowerlakylaminocarbonyl, cycloalkylaminocarbonyl,loweralkylphenylcarbonyl,haloloweralkylsulfonylloweralkyloxyphenylcarbonyl, andnitrophenylcarbonyl and R₁ and R₃ are selected independently from thegroup consisting of optionally substituted cycloalkyl, cycloheteroalkyl,(cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl include those wherein R₁and R₃ are selected independently from the group consisting ofoptionally substituted aryl and aralkyl, at least one of R₁ and R₃ issubstituted with at least one hydroxyl or thio group, and at least oneof R₁ and R₃ is selected independently from the group consisting ofphenyl, phenyloxyloweralkyl, and phenylloweralkyl, and at least one ofR₁ and R₃ is substituted optionally with a substituent selected from thegroup consisting of halogen, loweralkyl, halolowerlalkyl, loweralkyloxy,halolowerlakyloxy, carboxy, loweralkyloxycarbonyl, aryloxycarbonyl,(cycloloweralkyl)oxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl,heteroaralkyloxycarbonyl, (heterocycloloweralkyl)oxycarbonyl,loweralkylsulfinyl, loweralkylsulfonyl, loweralkylthio, arylthio,loweralkylcarbonyloxy, arylcarbonyloxy, aralkycarbonyloxy,heteroarylcarbonyloxy, heteroaralkylcarbonyloxy,(cycloloweralkyl)carbonyloxy, (heterocycloloweralkyl)carbonyloxy,aminocarbonyl, loweraklylaminocarbonyl, arylaminocarbonyl,aralkylaminocarbonyl, heteroarylaminocarbonyl, andheteroaralkylaminocarbonyl. Yet more detailed embodiments are thosepyrazoles having this substituent pattern wherein R₄ is selected fromthe group consisting of hydrogen and optionally substituted loweralkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloheteroalkyl,loweralkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,cycloalkylcarbonyl, cycloheteroalkylcarbonyl, aralkycarbonyl,heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl,(cycloheteroalkyl)alkylcarbonyl, loweralkylaminocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl,heteroaralkylaminocarbonyl, cycloalkylaminocarbonyl,(cycloalkyl)alkylaminocarbonyl, cycloheteroalkylaminocarbonyl,(cycloheteroalkyl)alkylaminocarbonyl, loweralkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl, cycloheteroalkylsulfonyl,aralkylsulfonyl, heteroaralkylsulfonyl, (cycloalkyl)alkylsulfonyl, and(cycloheteroalkyl)alkylsulfonyl.

[0081] In a second aspect, the present invention provide compoundshaving the general structures shown below:

[0082] and their pharmaceutically acceptable salts. X₅ is -(X₁₀)_(n)-,wherein n is an integer between 1 and 3 and X₁₀, for each value of n, isselected independently from the group consisting of oxygen, —SO_(x)—where x is and integer between 0 and 2, nitrogen, nitrogen substitutedwith optionally substituted loweralkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, arylcarbonyl, alkylcarbonyl, aralkylcarbonyl,heteroarylcarbonyl, heteroaralkylcarbonyl, and methylene or methine,each optionally substituted from the group consisting of halo, cyano,nitro, thio, amino, carboxyl, formyl, and optionally substitutedloweralkyl, loweralkylcarbonyloxy, arylcarbonyloxy,heteroarylcarbonyloxy, cycloalkylcarbonyloxy,cycloheteroalkylcarbonyloxy, aralkycarbonyloxy,heteroaralkylcarbonyloxy, (cycloalkyl)alkylcarbonyloxy,(cycloheteroalkyl)alkylcarbonyloxy, loweralkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, cycloalkylcarbonyl, cycloheteroalkylcarbonyl,aralkycarbonyl, heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl,(cycloheteroalkyl)alkylcarbonyl, loweralkylaminocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl,heteroaralkylaminocarbonyl, loweralkylcarbonylamino, arylcarbonylamino,heteroarylcarbonylamino, cycloalkylcarbonylamino,cycloheteroalkylcarbonylamino, aralkylcarbonylamino,heteroaralkylcarbonylamino, (cycloalkyl)alkylcarbonylamino,(cycloheteroalkyl)alkylcarbonylamino, loweralkylamino, arylamino,aralkylamino, heteroarylamino, heteroaralkylamino, loweralkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl,cycloheteroalkylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl,(cycloalkyl)alkylsulfonyl, (cycloheteroalkyl)alkylsulfonyl,loweralkylsulfinyl, arylsulfinyl, heteroarylsulfinyl,cycloalkylsulfinyl, cycloheteroalkylsulfinyl, aralkylsulfinyl,heteroaralkylsulfinyl, (cycloalkyl)alkylsulfinyl,(cycloheteroalkyl)alkylsulfinyl, loweralkyloxy, aryloxy, heteroaryloxy,cycloalkyloxy, cycloheteroalkyloxy, aralkyloxy, heteroaralkyloxy,(cycloalkyl)alkyloxy, and (cycloheteroalkyl)alkyloxy, loweralkylthio,arylthio, heteroarylthio, cycloalkylthio, cycloheteroalkylthio,aralkylthio, heteroaralkylthio, cycloalkyl)alkylthio,(cycloheteroalkyl)alkylthio, loweralkylthiocarbonyl, arylthiocarbonyl,heteroarylthiocarbonyl, cycloalkylthiocarbonyl,cycloheteroalkylthiocarbonyl, aralkythiocarbonyloxlthiocarbonyl,heteroaralkylthiocarbonyl, (cycloalkyl)alkylthiocarbonyl,(cycloheteroalkyl)alkylthiocarbonyl, loweralkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, cycloalkyloxycarbonyl,cycloheteroalkyloxycarbonyl, aralkyoxycarbonyloxloxycarbonyl,heteroaralkyloxycarbonyl, (cycloalkyl)alkyloxycarbonyl,(cycloheteroalkyl)alkyloxycarbonyl, iminoloweralkyl, iminocycloalkyl,iminocycloheteroalkyl, iminoaralkyl, iminoheteroaralkyl,(cycloalkyl)iminoalkyl, and (cycloheteroalkyl)iminoalkyl. X₆-X₉ areselected independently from the group consisting of oxygen, sulfur,sulfinyl, nitrogen, and optionally substituted methine. R₅ is selectedfrom the group consisting of hydrogen, carboxyl, formyl, and optionallysubstituted loweralkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,cycloalkyl, cycloheteroalkyl, loweralkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, cycloalkylcarbonyl, cycloheteroalkylcarbonyl,aralkycarbonyl, heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl,(cycloheteroalkyl)alkylcarbonyl, loweralkylaminocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl,heteroaralkylaminocarbonyl, cycloalkylaminocarbonyl,(cycloalkyl)alkylaminocarbonyl, cycloheteroalkylaminocarbonyl,(cycloheteroalkyl)alkylaminocarbonyl, loweralkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl, cycloheteroalkylsulfonyl,aralkylsulfonyl, heteroaralkylsulfonyl, (cycloalkyl)alkylsulfonyl,cycloheteroalkyl)alkylsulfonyl, loweralkylsulfinyl, arylsulfinyl,heteroarylsulfinyl, cycloalkylsulfinyl, cycloheteroalkylsulfinyl,aralkylsulfinyl, heteroaralkylsulfinyl, (cycloalkyl)alkylsulfinyl,cycloheteroalkyl)alkylsulfinyl, arylthiocarbonyl,heteroarylthiocarbonyl, cycloalkylthiocarbonyl,cycloheteroalkylthiocarbonyl, aralkythiocarbonyloxythiocarbonyl,heteroaralkylthiocarbonyl, (cycloalkyl)alkylthiocarbonyl,(cycloheteroalkyl)alkylthiocarbonyl, loweralkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, cycloalkyloxycarbonyl,cycloheteroalkyloxycarbonyl, aralkyoxycarbonyloxloxycarbonyl,heteroaralkyloxycarbonyl, (cycloalkyl)alkyloxycarbonyl,(cycloheteroalkyl)alkyloxycarbonyl, carboxamidino,loweralkylcarboxamidino, arylcarboxamidino, aralkylcarboxamidino,heteroarylcarboxamidino, heteroaralkylcarboxamidino,cycloalkylcarboxamidino, cycloheteroalkylcarboxamindino R₆ is selectedfrom the group consisting of optionally substituted loweralkyl, aryl,heteroaryl, cycloalkyl, cycloheteroalkyl, aralkyl, heteroaralkyl,(cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl

[0083] Some embodiments of the present invention include those fusedring structures having the general form shown above for which n is 1 andX₁₀ is selected from the group consisting of nitrogen, optionallysubstituted nitrogen, and optionally substituted methylene or methine.Such embodiments will be recognized as including ring systems that arecompletely delocalized as well as ring systems that are not completelydelocalized. More specific embodiments include those for which n is 1and X₁₀ is selected from the group consisting of nitrogen, optionallysubstituted nitrogen, and optionally substituted methylene or methineand R₆ is selected from the group consisting of optionally substitutedaryl, heteroaryl, aralkyl and heteroaralkyl. Still more specificembodiments include those for which n is 1 and X₁₀ is selected from thegroup consisting of nitrogen, optionally substituted nitrogen, andoptionally substituted methylene or methine and R₆ is optionallysubstituted aryl or aralkyl. Also included are embodiments of theabove-illustrated fused-ring ring pyrazoles in which n is 1 and X₁₀ isselected from the group consisting of nitrogen, optionally substitutednitrogen, and optionally substituted methylene or methine, R₆ isoptionally substituted aryl or aralkyl, and R₆ includes at least onehydroxyl, thio, or optionally substituted loweralkyloxy, aryloxy,heteroaryloxy, loweralkylthio, arylthio, heteroarylthio,loweralkylcarbonyl, arylcarbonyl, or heteroarylcarbonyl moiety.

[0084] In some embodiments for which n is 1 and X₁₀ is selected from thegroup consisting of nitrogen, optionally substituted nitrogen, andoptionally substituted methylene or methine, R₆ is selected from thegroup consisting of optionally substituted aryl, heteroaryl, aralkyl,and heteroaralkyl, and R₆ includes at least one hydroxyl, thio, oroptionally substituted loweralkyloxy, aryloxy, heteroaryloxy,loweralkylthio, arylthio, heteroarylthio, loweralkylcarbonyl,arylcarbonyl, or heteroarylcarbonyl moiety, R₆ is selected from thegroup consisting of phenyl, phenyloxyloweralkyl, and phenylloweralkyl.The present invention further includes compounds having thesesubstituents wherein R₆ is further substituted optionally with a moietyselected from the group consisting of halogen, loweralkyl,halolowerlalkyl, loweralkyloxy, halolowerlakyloxy, carboxy,loweralkyloxycarbonyl, aryloxycarbonyl, (cycloloweralkyl)oxycarbonyl,aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl,(heterocycloloweralkyl)oxycarbonyl, loweralkylsulfinyl,loweralkylsulfonyl, loweralkylthio, arylthio, loweralkylcarbonyloxy,arylcarbonyloxy, aralkycarbonyloxy, heteroarylcarbonyloxy,heteroaralkylcarbonyloxy, (cycloloweralkyl)carbonyloxy,(heterocycloloweralkyl)carbonyloxy, aminocarbonyl,loweraklylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl,heteroarylaminocarbonyl, and heteroaralkylaminocarbonyl.

[0085] The present invention also includes fused-ring pyrazolederivatives as illustrated above in which n is 1 and X₁₀ is selectedfrom the group consisting of nitrogen, optionally substituted nitrogen,and optionally substituted methylene or methine, R₆ is selected from thegroup consisting of phenyl, phenyloxyloweralkyl, and phenylloweralkyl,R₆ includes at least one hydroxyl, thio, or optionally substitutedloweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio,heteroarylthio, loweralkylcarbonyl, arylcarbonyl, or heteroarylcarbonylmoiety, R₆ is further substituted optionally with a moiety selected fromthe group consisting of halogen, loweralkyl, halolowerlalkyl,loweralkyloxy, halolowerlakyloxy, carboxy, loweralkyloxycarbonyl,aryloxycarbonyl, (cycloloweralkyl)oxycarbonyl, aralkyloxycarbonyl,heteroaryloxycarbonyl, heteroaralkyloxycarbonyl,(heterocycloloweralkyl)oxycarbonyl, loweralkylsulfinyl,loweralkylsulfonyl, loweralkylthio, arylthio, loweralkylcarbonyloxy,arylcarbonyloxy, aralkycarbonyloxy, heteroarylcarbonyloxy,heteroaralkylcarbonyloxy, (cycloloweralkyl)carbonyloxy,(heterocycloloweralkyl)carbonyloxy, aminocarbonyl,loweraklylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl,heteroarylaminocarbonyl, and heteroaralkylaminocarbonyl, and R₅ isselected from the group consisting of hydrogen and optionallysubstituted loweralkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,cycloalkyl, cycloheteroalkyl, loweralkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, cycloalkylcarbonyl, cycloheteroalkylcarbonyl,aralkycarbonyl, heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl,(cycloheteroalkyl)alkylcarbonyl, loweralkylaminocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl,heteroaralkylaminocarbonyl, cycloalkylaminocarbonyl,(cycloalkyl)alkylaminocarbonyl, cycloheteroalkylaminocarbonyl,(cycloheteroalkyl)alkylaminocarbonyl, loweralkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl, cycloheteroalkylsulfonyl,aralkylsulfonyl, heteroaralkylsulfonyl, cycloalkyl)alkylsulfonyl, and(cycloheteroalkyl)alkylsulfonyl.

[0086] Still other embodiments of the present invention include fusedring compounds of the general formula shown above or which n is 2 andeach X₁₀ is selected independently from the group consisting ofnitrogen, optionally substituted nitrogen, optionally substitutedmethylene, and optionally substituted methine. Again, these embodimentsinclude fully aromatic and partly aromatic ring systems. More particularembodiments are those for which n is 2 and each X₁₀ is selectedindependently from the group consisting of nitrogen, optionallysubstituted nitrogen, optionally substituted methylene, and optionallysubstituted methine and R₆ is selected from the group consisting ofoptionally substituted aryl, heteroaryl, aralkyl, and heteroaralkyl.Still more particular embodiments having the structural pattern justdescribed include those in which R₆ is optionally substituted aryl oraralkyl.

[0087] In other embodiments of the invention having the general fusedring structures shown for which n is 2 and each X₁₀ is selectedindependently from the group consisting of nitrogen, optionallysubstituted nitrogen, optionally substituted methylene, and optionallysubstituted methine, R₆ is selected from the group consisting ofoptionally substituted aryl, heteroaryl, aralkyl, and heteroaralkyl,more specifically wherein R₆ is optionally substituted aryl or aralkyl,are those for which R₆ includes at least one hydroxyl, thio, oroptionally substituted loweralkyloxy, aryloxy, heteroaryloxy,loweralkylthio, arylthio, heteroarylthio, loweralkylcarbonyl,arylcarbonyl, or heteroarylcarbonyl moiety. More specific embodimentsare those in which n, and X₁₀ have the values and identities justdescribed, R₆ is selected from the group consisting of optionallysubstituted aryl, heteroaryl, aralkyl, and heteroaralkyl, morespecifically R₆ is optionally substituted aryl or aralkyl, and R₆includes at least one hydroxyl, thio, or optionally substitutedloweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio,heteroarylthio, loweralkylcarbonyl, arylcarbonyl, or heteroarylcarbonylmoiety, wherein R₆ is selected from the group consisting of phenyl,phenyloxyloweralkyl, and phenylloweralkyl. More specific embodimentshaving this substituent pattern include those wherein R₆ is furthersubstituted optionally with a moiety selected from the group consistingof halogen, loweralkyl, halolowerlalkyl, loweralkyloxy,halolowerlakyloxy, carboxy, loweralkyloxycarbonyl, aryloxycarbonyl,(cycloloweralkyl)oxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl,heteroaralkyloxycarbonyl, (heterocycloloweralkyl)oxycarbonyl,loweralkylsulfinyl, loweralkylsulfonyl, loweralkylthio, arylthio,loweralkylcarbonyloxy, arylcarbonyloxy, aralkycarbonyloxy,heteroarylcarbonyloxy, heteroaralkylcarbonyloxy,(cycloloweralkyl)carbonyloxy, (heterocycloloweralkyl)carbonyloxy,aminocarbonyl, loweraklylaminocarbonyl, arylaminocarbonyl,aralkylaminocarbonyl, heteroarylaminocarbonyl, andheteroaralkylaminocarbonyl. Still more specific embodiments includethose for which n is 2 and each X₁₀ is selected independently from thegroup consisting of nitrogen, optionally substituted nitrogen,optionally substituted methylene, and optionally substituted methine, R₆is selected from the group consisting of optionally substituted aryl,heteroaryl, aralkyl, and heteroaralkyl, more specifically R₆ isoptionally substituted aryl or aralkyl, and R₆ includes at least onehydroxyl, thio or optionally substituted loweralkyloxy, aryloxy,heteroaryloxy, loweralkylthio, arylthio, heteroarylthio,loweralkylcarbonyl, arylcarbonyl, or heteroarylcarbonyl moiety, whereinR₆ is selected from the group consisting of phenyl, phenyloxyloweralkyl,and phenylloweralkyl, more specifically wherein R₆ is furthersubstituted optionally with a moiety selected from the group consistingof halogen, loweralkyl, halolowerlalkyl, loweralkyloxy,halolowerlakyloxy, carboxy, loweralkyloxycarbonyl, aryloxycarbonyl,(cycloloweralkyl)oxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl,heteroaralkyloxycarbonyl, (heterocycloloweralkyl)oxycarbonyl,loweralkylsulfinyl, loweralkylsulfonyl, loweralkylthio, arylthio,loweralkylcarbonyloxy, arylcarbonyloxy, aralkycarbonyloxy,heteroarylcarbonyloxy, heteroaralkylcarbonyloxy,(cycloloweralkyl)carbonyloxy, heterocycloloweralkyl)carbonyloxy,aminocarbonyl, loweraklylaminocarbonyl, arylaminocarbonyl,aralkylaminocarbonyl, heteroarylaminocarbonyl, andheteroaralkylaminocarbonyl, and R₅ is selected from the group consistingof hydrogen and optionally substituted loweralkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, cycloalkyl, cycloheteroalkyl,loweralkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,cycloalkylcarbonyl, cycloheteroalkylcarbonyl, aralkycarbonyl,heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl,(cycloheteroalkyl)alkylcarbonyl, loweralkylaminocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl,heteroaralkylaminocarbonyl, cycloalkylaminocarbonyl,(cycloalkyl)alkylaminocarbonyl, cycloheteroalkylaminocarbonyl,(cycloheteroalkyl)alkylaminocarbonyl, loweralkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl, cycloheteroalkylsulfonyl,aralkylsulfonyl, heteroaralkylsulfonyl, (cycloalkyl)alkylsulfonyl, and(cycloheteroalkyl)alkylsulfonyl.

[0088] In another embodiment, the present invention provides fused ringsstructures shown above in which X₆-X₉ are selected independently fromthe group consisting of nitrogen and optionally substituted methine.More particular embodiments are those for which at least one of X₆-X₉ ismethine substituted with a moiety selected from the group consisting ofloweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio,heteroarylthio, loweralkylcarbonyl, arylcarbonyl, andheteroarylcarbonyl. Still more particular fused ring embodiments arethose for which X₆-X₉ are selected independently from the groupconsisting of nitrogen and optionally substituted methine, at least oneof X₆-X₉ is methine substituted with a moiety selected from the groupconsisting of loweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio,arylthio, heteroarylthio, loweralkylcarbonyl, arylcarbonyl, andheteroarylcarbonyl and X₇ is methine substituted with hydroxy orloweralkyloxy. Other more specific embodiments are those in which X₆-X₉are selected independently from the group consisting of nitrogen andoptionally substituted methine, at least one of X₆-X₉ is methinesubstituted with a moiety selected from the group consisting ofloweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio,heteroarylthio, loweralkylcarbonyl, arylcarbonyl, andheteroarylcarbonyl, n is 1 and X₁₀ is selected from the group consistingof nitrogen, optionally substituted nitrogen, and optionally substitutedmethylene or methine.

[0089] Still more specific embodiments include those for which X₆-X₉, n,and X₁₀ have the values just defined and R₆ is selected from the groupconsisting of optionally substituted aryl, heteroaryl, aralkyl, andheteroaralkyl. In yet more specific embodiments, X₆-X₉, n and X₁₀ havethe values just defined R₆ is selected from the group consisting ofoptionally substituted aryl, heteroaryl, aralkyl, and heteroaralkyl, andmore particularly R₆ is optionally substituted aryl or aralkyl. Yet morespecific embodiments are those for which X₆-X₉, n and X₁₀ have thevalues just defined R₆ is selected from the group consisting ofoptionally substituted aryl, heteroaryl, aralkyl, and heteroaralkyl,more particularly R₆ is optionally substituted aryl or aralkyl, and R₆includes at least one hydroxyl, thio, or optionally substitutedloweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio,heteroarylthio, loweralkylcarbonyl, arylcarbonyl, or heteroarylcarbonylmoiety. Other embodiments are those for which n and X₁₀ have the valuesjust defined R₆ is selected from the group consisting of optionallysubstituted aryl, heteroaryl, aralkyl, and heteroaralkyl, moreparticularly R₆ is optionally substituted aryl or aralkyl, such that R₆includes at least one hydroxyl, thio, or optionally substitutedloweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio,heteroarylthio, loweralkylcarbonyl, arylcarbonyl, or heteroarylcarbonylmoiety, and further R₆ is selected from the group consisting of phenyl,phenyloxyloweralkyl, and phenylloweralkyl. Yet more particularembodiments having the latter substituent pattern are those in which R₆is further substituted optionally with a moiety selected from the groupconsisting of halogen, loweralkyl, halolowerlalkyl, loweralkyloxy,halolowerlakyloxy, carboxy, loweralkyloxycarbonyl, aryloxycarbonyl,(cycloloweralkyl)oxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl,heteroaralkyloxycarbonyl, (heterocycloloweralkyl)oxycarbonyl,loweralkylsulfinyl, loweralkylsulfonyl, loweralkylthio, arylthio,loweralkylcarbonyloxy, arylcarbonyloxy, aralkycarbonyloxy,heteroarylcarbonyloxy, heteroaralkylcarbonyloxy,(cycloloweralkyl)carbonyloxy, (heterocycloloweralkyl)carbonyloxy,aminocarbonyl, loweraklylaminocarbonyl, arylaminocarbonyl,aralkylaminocarbonyl, heteroarylaminocarbonyl, andheteroaralkylaminocarbonyl. Still more particular embodiments havingX₆-X₉ are selected independently from the group consisting of nitrogenand optionally substituted methine, at least one of X₆-X₉ is methinesubstituted with a moiety selected from the group consisting ofloweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio,heteroarylthio, loweralkylcarbonyl, arylcarbonyl, andheteroarylcarbonyl, n is 1 and X₁₀ is selected from the group consistingof nitrogen, optionally substituted nitrogen, and optionally substitutedmethylene or methine, R₆ is selected from the group consisting ofoptionally substituted aryl, heteroaryl, aralkyl, and heteroaralkyl,more particularly R₆ is optionally substituted aryl or aralkyl, suchthat R₆ includes at least one hydroxyl, thio, or optionally substitutedloweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio,heteroarylthio, loweralkylcarbonyl, arylcarbonyl, or heteroarylcarbonylmoiety, further such that R₆ is selected from the group consisting ofphenyl, phenyloxyloweralkyl, and phenylloweralkyl and R₆ is furthersubstituted optionally with a moiety selected from the group consistingof halogen, loweralkyl, halolowerlalkyl, loweralkyloxy,halolowerlakyloxy, carboxy, loweralkyloxycarbonyl, aryloxycarbonyl,(cycloloweralkyl)oxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl,heteroaralkyloxycarbonyl, (heterocycloloweralkyl)oxycarbonyl,loweralkylsulfinyl, loweralkylsulfonyl, loweralkylthio, arylthio,loweralkylcarbonyloxy, arylcarbonyloxy, aralkycarbonyloxy,heteroarylcarbonyloxy, heteroaralkylcarbonyloxy,(cycloloweralkyl)carbonyloxy, (heterocycloloweralkyl)carbonyloxy,aminocarbonyl, loweraklylaminocarbonyl, arylaminocarbonyl,aralkylaminocarbonyl, heteroarylaminocarbonyl, andheteroaralkylaminocarbonyl, wherein R₅ is selected from the groupconsisting of hydrogen and optionally substituted loweralkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloheteroalkyl,loweralkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,cycloalkylcarbonyl, cycloheteroalkylcarbonyl, aralkycarbonyl,heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl,(cycloheteroalkyl)alkylcarbonyl, loweralkylaminocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl,heteroaralkylaminocarbonyl, cycloalkylaminocarbonyl,(cycloalkyl)alkylaminocarbonyl, cycloheteroalkylaminocarbonyl,(cycloheteroalkyl)alkylaminocarbonyl, loweralkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl, cycloheteroalkylsulfonyl,aralkylsulfonyl, heteroaralkylsulfonyl, (cycloalkyl)alkylsulfonyl, and(cycloheteroalkyl)alkylsulfonyl.

[0090] Yet other embodiments of the invention including the compounds ofthe general formula above are those in which X₆-X₉ are selectedindependently from the group consisting of nitrogen and optionallysubstituted methine, at least one of X₆-X₉ is methine substituted with amoiety selected from the group consisting of loweralkyloxy, aryloxy,heteroaryloxy, loweralkylthio, arylthio, heteroarylthio,loweralkylcarbonyl, arylcarbonyl, and heteroarylcarbonyl, n is 2 andeach X₁₀ is selected independently from the group consisting ofnitrogen, optionally substituted nitrogen, optionally substitutedmethylene, and optionally substituted methine. More specific embodimentsare those in which X₆-X₉ are selected independently from the groupconsisting of nitrogen and optionally substituted methine, at least oneof X₆-X₉ is methine substituted with a moiety selected from the groupconsisting of loweralkyloxy, aryloxy, heteroaryloxy, loweralklthio,arylthio, heteroarylthio, loweralkylcarbonyl, arylcarbonyl, andheteroarylcarbonyl, n is 2 and each X₁₀ is selected independently fromthe group consisting of nitrogen, optionally substituted nitrogen,optionally substituted methylene, and optionally substituted methine,and R₆ is selected from the group consisting of optionally substitutedaryl, heteroaryl, aralkyl, and heteroaralkyl. Still more specificembodiments include those for which X₆-X₉, n, and X₁₀ have the valuesjust defined R₆ is selected from the group consisting of optionallysubstituted aryl, heteroaryl, aralkyl, and heteroaralkyl and, moreparticularly, R₆ is optionally substituted aryl or aralkyl. In yet morespecific embodiments, X₆-X₉, n and X₁₀ have the values just defined R₆is selected from the group consisting of optionally substituted aryl,heteroaryl, aralkyl, and heteroaralky, more particularly, R₆ isoptionally substituted aryl or aralkyl, and R₆ includes at least onehydroxyl, thio, or optionally substituted loweralkyloxy, aryloxy,heteroaryloxy, loweralkylthio, arylthio, heteroarylthio,loweralkylcarbonyl, arylcarbonyl, or heteroarylcarbonyl moiety. Yet morespecific embodiments are those for which X₆-X₉, n and X₁₀ have thevalues just defined R₆ is selected from the group consisting ofoptionally substituted aryl, heteroaryl, aralkyl, and heteroaralky, moreparticularly, R₆ is optionally substituted aryl or aralkyl, and R₆includes at least one hydroxyl, thio, or optionally substitutedloweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio,heteroarylthio, loweralkylcarbonyl, arylcarbonyl, or heteroarylcarbonylmoiety, and R₆ is selected from the group consisting of phenyl,phenyloxyloweralkyl, and phenylloweralkyl. Other embodiments are thosefor which X₆-X₉, n and X₁₀ have the values just defined, R₆ is selectedfrom the group consisting of optionally substituted aryl, heteroaryl,aralkyl, and heteroaralky, more particularly, R₆ is optionallysubstituted aryl or aralkyl, and R₆ includes at least one hydroxyl,thio, or optionally substituted loweralkyloxy, aryloxy, heteroaryloxy,loweralkylthio, arylthio, heteroarylthio, loweralkylcarbonyl,arylcarbonyl, or heteroarylcarbonyl moiety, such that R₆ is selectedfrom the group consisting of phenyl, phenyloxyloweralkyl, andphenylloweralkyl, and R₆ is further substituted optionally with a moietyselected from the group consisting of halogen, loweralkyl,halolowerlalkyl, loweralkyloxy, halolowerlakyloxy, carboxy,loweralkyloxycarbonyl, aryloxycarbonyl, (cycloloweralkyl)oxycarbonyl,aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl,(heterocycloloweralkyl)oxycarbonyl, loweralkylsulfinyl,loweralkylsulfonyl, loweralkylthio, arylthio, loweralkylcarbonyloxy,arylcarbonyloxy, aralkycarbonyloxy, heteroarylcarbonyloxy,heteroaralkylcarbonyloxy, (cycloloweralkyl)carbonyloxy,(heterocycloloweralkyl)carbonyloxy, aminocarbonyl,loweraklylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl,heteroarylaminocarbonyl, and heteroaralkylaminocarbonyl. Yet otherembodiments of the compounds having the fused ring structures shownabove have the values X₆-X₉, n, X₁₀, and R₆ just described above andfurther R₅ is selected from the group consisting of hydrogen andoptionally substituted loweralkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, cycloalkyl, cycloheteroalkyl, loweralkylcarbonyl,arylcarbonyl, heteroarylcarbonyl, cycloalkylcarbonyl,cycloheteroalkylcarbonyl, aralkycarbonyl, heteroaralkylcarbonyl,(cycloalkyl)alkylcarbonyl, (cycloheteroalkyl)alkylcarbonyl,loweralkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl,heteroarylaminocarbonyl, heteroaralkylaminocarbonyl,cycloalkylaminocarbonyl, (cycloalkyl)alkylaminocarbonyl,cycloheteroalkylaminocarbonyl, (cycloheteroalkyl)alkylaminocarbonyl,loweralkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,cycloalkylsulfonyl, cycloheteroalkylsulfonyl, aralkylsulfonyl,heteroaralkylsulfonyl, (cycloalkyl)alkylsulfonyl, and(cycloheteroalkyl)alkylsulfonyl.

[0091] 4.3 Synthesis of the Compounds of the Invention

[0092] The compounds of the present invention can be synthesized usingtechniques and materials known to those of skill in the art (Carey andSundberg 1983; Carey and Sundberg 1983; Greene and Wuts 1991; March1992). Starting materials for the compounds of the invention may beobtained using standard techniques and commercially available precursormaterials, such as those available from Aldrich Chemical Co. (Milwaukee,Wis.), Sigma Chemical Co. (St. Louis, Mo.), Lancaster Synthesis(Windham, N.H.), Apin Chemicals, Ltd. (New Brunswick, N.J.), RyanScientific (Columbia, S.C.), Maybridge (Cornwall, England), Arcos(Pittsburgh, Pa.), and Trans World Chemicals (Rockville, Md.)

[0093] The procedures described herein for synthesizing the compounds ofthe invention may include one or more steps of protection anddeprotection (e.g., the formation and removal of acetal groups) (Greeneand Wuts 1991). In addition, the synthetic procedures disclosed belowcan include various purifications, such as column chromatography, flashchromatography, thin-layer chromatography (“TLC”), recrystallization,distillation, high-pressure liquid chromatography (“HPLC”) and the like.Also, various techniques well known in the chemical arts for theidentification and quantification of chemical reaction products, such asproton and carbon-13 nuclear magnetic resonance (¹H and ¹³C NMR),infrared and ultraviolet spectroscopy (“IR” and “UV”), X-raycrystallography, elemental analysis (“EA”). HPLC and mass spectroscopy(“MS”) can be used for identification, quantitation and purification aswell.

[0094] Scheme 1 is a general scheme for synthesis of pyrazoles.

[0095] Step A is a Claisen-type condensation, in which X is a leavinggroup such as —OR (R=alkyl, aryl, arlkyl, heteroaryl, or heteroaralkyl),or halogen. When X is —OR and R is alkyl (e.g., X is methoxy or ethoxy)the reaction of 1a and 1b to produce 1c can be done using proceduresknown to those of skill in the organic chemistry arts (Tietze and Eicher1989). When X is halogen, e.g., Cl, a typical procedure involvesdeprotonation of ketone 1a with a base such as lithiumbis(trimethylsilyl)amide (LiHMDS) followed by addition of 1b. Suitablesolvents for performing such reactions will be familiar to those ofskill in the organic chemistry arts. Examples of suitable solventsinclude ether-type solvents such as tetrahydrofuran (“THF”), diethylether (H₃CH₂COCH₂CH₃), or aliphatic and aromatic hydrocarbon solventssuch as cyclohexane (C₆H₁₂) and toluene (C₇H₈). Typical reactiontemperatures range from −78° C. to +25° C. and the reaction times from 6hours (“h”) to 20 h. Step B is a cycloaddition reaction to form thepyrazole heterocycle. This can be done using the known Knorr pyrazolesynthesis method. Typically, 1c, hydrazine (NH₂NHR₄) and catalyticamount of HCl (aq.) in ethanol are heated to reflux overnight. Removalof the solvent followed by routine extraction yields the crude material,which can be purified to afford pure compound 1d. If R₁ and R₂ are notidentical, then a mixture of regioisomers is formed. In some cases,protecting groups have to be removed to obtain the desired compound(step not shown). Protection and deprotection will depend greatly on thechemical properties of the molecule and its functional groups;appropriate methods for protection and deprotection are well known inthe organic chemistry arts (Greene and Wuts 1991). For example, when R₁is methoxyphenyl, three methods can be used for demethylation: 1)reaction of aqueous hydrogen bromide (HBr) and glacial acetic acid with1d with heating to 100-120° C. for 6 to 16 h; 2) reaction of ethanethiol, aluminum trichloride, and 1d in dichloroethane with stirring atroom temperature (“rt”) for 16 to 72 h; or 3) stirring boron tribromidewith 1d in dichloromethane at room temperature overnight.

[0096] Scheme 2 describes an alternative method to synthesize compound1c of Scheme 1.

[0097] Step A above can be performed using various methods familiar tothose of skill in the organic chemistry arts. For example, at leastthree well known methods can be used to convert 3a to 1c: 1)deprotonation of 3a with a base such as sodium hydride (NaH) in anaprotic solvent such as dimethylformamide (“DMF”) or THF, followed byreaction of the resulting anion with an electrophile R₃X, wherein X is aleaving group such as halogen or MsO; or 2) compound 3a is reacted withR₃X, potassium carbonate and tetrabutylammonium bromide in DMF whilestirring at rt −100° C. for 6 to 24 h. If R₃ is paraalkyloxyphenyl, thena plumbate method can be applied (Craig, Holder et al. 1979; Pinhey,Holder et al. 1979).

[0098] Scheme 3 describes an alternative method to synthesize compound1d in Scheme 1.

[0099] Pyrazole 3a was synthesized (Step A) by mixing diketone 1c withexcess hydrazine and catalytic amount of a protonic acid such as HCl oracetic acid. The solvent can be ethanol, methanol, or DMSO; the reactionis usually performed at temperatures from 60-100° C. and completedwithin 18 h. Alkylation of 4a (Step B) can be carried out using knowntechniques, such as exemplified by the following two methods (bothmethods generate a mixture of regioisomers). In one method, a mixture of3a, cesium carbonate and an alkylating agent R₅X (wherein X=leavinggroup such as a halide or MsO) in DMF was heated to 100° C. overnight. Awork-up under aqueous conditions, followed by extraction andpurification (if necessary), affords the product 1d. In a second method4a is deprotonated using0 sodium hydride in DMF or THF, followed byaddition of an electrophile such as an alkyl halide, sulfonyl chloride,or acyl chloride. The reaction is typically performed at a temperaturebetween rt and 60° C. and completed within 16 h.

[0100] Formation of pyrazole 4a from 1,3-diketone 3a can be completedusing the procedures described in Scheme 1 and in Scheme 3. Brominationof pyrazole 4a (Step B) can be performed by addition of bromine to achloroform solution solution of 4a, at a reaction temperature fromrt−55° C. from 0.5 to 2 h. A variety of R₂ substituents (Step C) can beintroduced to 4-bromopyrazole 4b by known methods. For example,metal-halogen exchange followed by trapping the resulting anion with anelectrophile can be used to attach R₃. This can be done, for example, byreaction of bromopyrazole 4b in THF solution at −78° C. with n-BuLi. Themixture is stirred at −78°C. for 1 h. The desired electrophilecorresponding to R₂ is then added, and the reaction is warmed from 0°C.-rt over a period between 2 to 16 h. Suitable electrophiles include,but are not limited to, the following: alkyl halides, disulfides,iodine, N-chlorosuccinimide, tosyl nitrile, ethyl chloroformate, acidchlorides, carbon dioxide, dimethylformamide, aldehydes, Weinreb amidesand sulfonyl chlorides. Alternatively, a 4-carboxypyrazole (ie.,R₃=—CO₂) can be obtained if carbon dioxide is used as the electrophile.The carboxylic acid can be further transformed to various esters,amides, and ketones. To form an amide at R₂, typical amide bondformation condition can be applied. For example, the correspondingcarboxylic acid can be activated with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (“EDC”) HCl salt,1-hydroxybenzotriazole (“HOBt”), and Hünig's base and mixed with aprimary or secondary amine in THF or DMF. The reaction is complete in 6to 16 hours at rt. Suzuki coupling can also be used to introduce aryland alkenyl moieties at R₃ (Miyaura, Author et al. 1979; Miyaura andSuzuki 1979). The Ullmann reaction can be used to introduce aryloxygroups at R₃ (Knight; Semmelhack, Author et al. ). Moieties having C—Nand C—O bonds at 4-position of pyrazole 4b can be achieved by applyingpalladium catalyzed coupling reactions (Palucki, Wolfe et al. 1996;Wolfe and Buchwald 1996; Wolfe, Wagaw et al. 1996).

[0101] Scheme 5 illustrates more specific modifications at 4-position ofthe pyrazole.

[0102] Starting material 5a can be synthesized by methods describedabove. The linker Z can be —CH₂—, —O—, —S—, —SO₂—, —NR′R″—, —(C═O)—,—(C═NOR)—, or the aryl group can be attached to the pyrazole coredirectly. In the Scheme above, R₃ is a phenol protecting group which canbe selectively removed (Greene and Wuts 1991). However, other suitablegroups such as, but not limited to, thiols, protected thiols, amines,and the like can be synthesized using analogous methodologies. Onespecific methodology is described with respect to Scheme 6 below where Zis —SO₂— or —(C═O)— and Y is O, S, or N. The index n can be 1, 2, or 3,and R₄ is —NR′R″ or —N(R′)(C=O)R″. In one example, sodium hydride wasmixed with HY(CH₂)_(n)R₄, to generate the nucleophile and added to 6a inTHF or DMF solution at a temperature from between rt and 60° C. andcompleted within 2 to 8 h.

[0103] Specific modifications at 5-position of the pyrazole can beperformed using the methodologies described with Scheme 7 below:

[0104] where E is alkyl, aryl, aralkyl, halo, cyano, amido, carboxy,sulfide, and sulfoxide. Starting material 7a can be synthesizedaccording to methods described above. The functional group E isintroduced using the methods described in Step C of Scheme 3 above.Modifications at the 4-position of the pyrazole can be made, forexample, using the methods described with respect to Scheme 8.

[0105] Starting material 8a was synthesized according to methodsdescribed in Scheme 1. Bromination at the methyl position was performedusing N-bromosuccinimide in carbon tetrachloride. Alkylation to formderivatives of 8c where R″ is —OR, —SR or —NRR′ can be conducted withappropriate nucleophile in a suitable solvent (e.g., DM or THF) attemperatures ranging between rt and 100° C.

[0106] The procedures described above can be applied to solid phasemethodologies as well. The actual implementation depends, of course, onthe details of the desired products and starting materials. One exampleof a suitable methodology, where R₁ is hydroxyphenyl, is shown in Scheme9.

[0107] In step A, commercially available hydroxylated Rink resin(Calbiochem, La Jolla, Calif.) is reacted with mesyl chloride andHünig's base in methylene chloride (CH₂Cl₂) at 0° C. with warming toroom temperature over a two-hour period. Next, 4-hydroxyacetophenone andHfinig's base are reacted with the resin product in methylene chlorideat room temperature overnight to provide resin-bound providesresin-bound ketone 9a. Reaction of the bound ketone with an esterbearing the R₃ substituent (R₃CO₂R) and base (e.g., potassiumtert-butoxide, t-BuOK and dibenzo- 18-crown-6) in a suitable solvent(e.g., THF) at 70° C. for six hours (Step B) provides diketone 9b.Deprotonation of 9b, using, e.g., tert-butyl ammonium iodide (“TBAI”)under mild conditions (70° C. overnight) and the R₂ substituent bearinga suitable leaving group (e.g., halogen, tosylate, mesylate) provides9c. Cyclization of 9c to form the desired pyrazole (resin-boundregioisomers 9d and 9e) can be performed by reaction of the bounddiketone with R₄NHNH₂ and Hünig's base in a suitable solvent (e.g.,dimethylsulfoxide, (“DMSO”)) at 70° C. for fifteen hours. Cleavage fromthe resin can be performed under mild conditions (e.g., reaction with 5%trifluoroacetic acid. (“TFA”) in methylene chloride) provides the finalproducts 9d and 9e.

[0108] 4.4 Biological Activity

[0109] The activities of the compounds of the invention to function asestrogen receptor agonists or antagonists can be determined using a widevariety of assays known to those having skill in the biochemistry,medicinal chemistry, and endochrinology arts. Several useful assays aredescribed generally in this Section 4.4. Specific examples are describedin Section 5.2 below.

[0110] 4.4.1 Assays for Estrogen Receptor Modulatng Activity In Vivo andEx Vivo

[0111] 4.4.1.1 Allen-Doisy Test for Estrogenicity

[0112] This test (described in greater detail in Section 5.2.1.1 below)is used to evaluate a test compound for estrogenic activity, and, morespecifically, the ability of a test compound to induce an estrogeniccornification of vaginal epithelium (Allen and Doisy 1923; Mühlbock1940; Terenius 1971). Test compounds are formulated and administeredsubcutaneously to mature, ovariectomized female rats in test groups. Inthe third week after bilateral ovariectomy, the rats are primed with asingle subcutaneous dose of estradiol to ensure maintenance ofsensitivity and greater uniformity of response. In the fourth week, 7days after priming, the test compounds are administered. The compoundsare given in three equal doses over two days (evening of the first dayand morning and evening of the second day). Vaginal smears are thenprepared twice daily for the following three days. The extent ofcornified and nucleated epithelial cells, as well as of leucocytes areevaluated for each of the smears.

[0113] 4.4.1.2 Anti-Allen-Doisy Test for Anti-Estrogenicity

[0114] This test (described in greater detail in Section 5.2.1.2 below)is used to evaluate a test compound for anti-estrogenic activity byobservation of comification of the vaginal epithelium of inovariectornized rats after administration of a test compound (Allen andDoisy 1923; Mühlbock 1940; Terenius 1971). Evaluation of anti-estrogenicactivity is performed using mature female rats which, two weeks afterbilateral ovariectomy, are treated with estradiol to induce acomification of the vaginal epithelial. This was followed byadministration of the test compound in a suitable formulation daily for10 days. Vaginal smears are prepared daily, starting on the first day oftest compound administration and proceeding until one day following thelast administration of test compound. The extent of comified andnucleated epithelial cells and leucocytes is evaluated for each of thesmears as above.

[0115] 4.4.1.3 Immature Rat Uterotrophic Bioassay for Estrogenicity andAnti-Estrogenicity

[0116] Changes in uterine weight in response to estrogenic stimulationcan be used to evaluate the estrogenic characteristics of test compoundson uterine tissues (Reel, Lamb et al. 1996; Ashby, Odum et al. 1997). Inone example, described in Section 5.2.1.3 below, immature female ratshaving low endogenous levels of estrogen are dosed with test compound(subcutaneously) daily for 3 days. Compounds are formulated asappropriate for subcutaneous injection. As a control, 17-beta-estradiolis administered alone to one dose group. Vehicle control dose groups arealso included in the study. Twenty-four hours after the last treatment,the animals are necropsied, and their uteri excised, nicked, blotted andweighed to. Any statistically significant increases in uterine weight ina particular dose group as compared to the vehicle control groupdemonstrate evidence of estrogenicity.

[0117] 4.4.1.4 Estrogen Receptor Antagonist Efficacy In MCF-7 XenograftModel

[0118] This test (described in detail in Section 5.2.1.4 below) is usedto evaluate the ability of a compound to antagonize the growth of anestrogen-dependent breast MCF-7 tumor in vivo. Female Ncr-nu mice areimplanted subcutaneously with an MCF-7 mammary tumor from an existing invivo passage. A 17-β-estradiol pellet is implanted on the side oppositethe tumor implant on the same day. Treatment with test compound beginswhen tumors have reached a certain minimum size (e.g., 75-200 mg). Thetest compound is administered subcutaneously on a daily basis and theanimals are subjected to daily mortality checks. Body weights and tumorvolume are determined twice a week starting the first day of treatment.Dosing continues until the tumors reach 1,000 mm³. Mice with tumorslarger than 4,000 mg, or with ulcerated tumors, are sacrificed prior tothe day of the study determination. The tumor weights of animals in thetreatment group are compared to those in the untreated control group aswell as those given the estradiol pellet alone.

[0119] 4.4.1.5 OVX Rat Model

[0120] This model evaluates the ability of a compound to reverse thedecrease in bone density and increase in cholesterol levels resultingfrom ovariectomy. One example of such a model is described in Section5.2.1.5. Three-month old female rats are ovariectomized, and testcompounds are administered daily by subcutaneous route beginning one daypost-surgery. Sham operated animals and ovariectomized animals withvehicle control administered are used as control groups. After 28 daysof treatment, the rats are weighed, the overall body weight gainsobtained, and the animals euthanized. Characteristics indicative ofestrogenic activity, such as blood bone markers (e.g., osteocalcin,bone-specific alkaline phosphatase), total cholesterol, and urinemarkers (e.g., deoxypyridinoline, creatinine) are measured in additionto uterine weight. Both tibiae and femurs are removed from the testanimals for analysis, such as the measurement of bone mineral density. Acomparison of the ovariectomized and test vehicle animals to the shamand ovariectomized control animals allows a determination of the tissuespecific estrogenic/anti-estrogenic effects of the test compounds.

[0121] 4.4.2 Assays for Estrogen Receptor Modulating Activity In Vkro

[0122] 4.4.2.1 ERα/ERβ Binding Assays

[0123] For evaluation of ERβ/ERβ receptor binding affinity, ahomogeneous scintillation proximity assay is used (described in Sections5.2.2.1 and 5.2.2.2 below). 96-well plates are coated with a solution ofeither ERα or ERβ. After coating, the plates are washed with PBS. Thereceptor solution is added to the coated plates, and the plates areincubated. For library screening, [³H]estradiol is combined with thetest compounds in the wells of the 96-well plate. Non-specific bindingof the radio-ligand is determined by adding estradiol to one of thewells as a competitor. The plates are gently shaken to mix the reagentsand a sample from each of the wells is then transferred to thepre-coated ERα or ERβ plates. The plates are sealed and incubated, andthe receptor-bound estradiol read directly after incubation using ascintillation counter to determine test compound activity. If estimatesof both bound and free ligand are desired, supernatant can be removedand counted separately in a liquid scintillation counter.

[0124] 4.4.2.2 ERα/ERβ Transactivation Assays

[0125] The estrogenicity of the compounds of the invention can beevaluated in an in vitro bioassay using Chinese hamster ovary (“CHO”)cells that have been stably co-transfected with the human estrogenreceptor (“hER”), the rat oxytocin promoter (“RO”) and the luciferasereporter gene (“LUC”) as described in Section 5.2.2.3 below. Theestrogen transactivation activity (potency ratio) of a test compound toinhibit transactivation of the enzyme luciferase as mediated by theestrogen receptor is compared with a standard and the pure estrogenantagonist.

[0126] 4.4.2.3 MCF-7 Cell Proliferaton Assays

[0127] MCF-7 cells are a common line of breast cancer cells used todetermine in vitro estrogen receptor agonist/antagonist activity(MacGregor and Jordan 1998). The effect of a test compound on theproliferation of MCF-7 cells, as measured by the incorporation of5-bromo-2′-deoxyuridine (“BrdU”) in a chemiluminescent assay format, canbe used to determine the relative agonist/antagonist activity of thetest compound. MCF-7 cells (ATCC HTB-22) are mainatmed in log-phaseculture. The cells are plated and incubated in phenol-free medium toavoid external sources of estrogenic stimulus (MacGregor and Jordan1998). The test compound is added at varying concentrations to determinean IC₅₀ for the compound. To determine agonist activity, the assaysystem is kept free of estrogen or estrogen-acting sources. To determineantagonist activity, controlled amounts of estrogen are added.

[0128] 4.5 Pharnaceutical Compositons

[0129] The compounds of the present invention can be used in the form ofsalts derived from inorganic or organic acids. These salts include, butare not limited to, the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepro-pionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemi-sulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-napth-alenesulfonate, oxalate, pamoate,pectinate, sulfate, 3-phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate.Also, any basic nitrogen-containing groups can be quaternized withagents such as loweralkyl halides, such as methyl, ethyl, propyl, andbutyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl,diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkylhalides like benzyl and phenethyl bromides, and others. Water oroil-soluble or dispersible products are thereby obtained.

[0130] Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulfuric acid, and phosphoric acid, and organic acidssuch as oxalic acid, maleic acid, succinic acid and citric acid. Basicaddition salts can be prepared in situ during the fmal isolation andpurification of the compounds of the invention, or separately byreacting carboxylic acid moieties with a suitable base such as thehydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia, or an organic primary, secondary ortertiary amine. Pharmaceutically acceptable salts include, but are notlimited to, cations based on the alkali and alkaline earth metals, suchas sodium, lithium, potassium, calcium, magnesium, aluminum salts andthe like, as well as nontoxic ammonium, quaternary ammonium, and aminecations, including, but not limited to ammonium, tetaamethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, ethylamine, and the like. Other representative organicamines useful for the formation of base addition salts includediethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazineand the like.

[0131] Compounds of the present invention can be administered in avariety of ways including enteral, parenteral and topical routes ofadministration. For example, suitable modes of administration includeoral, subcutaneous, transdermal, transmucosal, iontophoretic,intravenous, intramuscular, intraperitoneal, intranasal, subdural,rectal, vaginal, and the like.

[0132] In accordance with other embodiments of the present invention,there is provided a composition comprising an estrogenreceptor-modulating compound of the present invention, together with apharmaceutically acceptable carrier or excipient.

[0133] Suitable pharmaceutically acceptable excipients includeprocessing agents and drug delivery modifiers and enhancers, such as,for example, calcium phosphate, magnesium stearate, talc,monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, dextrose,hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidinone, low melting waxes,ion exchange resins, and the like, as well as combinations of any two ormore thereof. Other suitable pharmaceutically acceptable excipients aredescribed in Remington's Pharmaceutical Sciences, Mack Pub. Co., NewJersey (1991), which is incorporated herein by reference.

[0134] Pharmaceutical compositions containing estrogen receptormodulating compounds of the present invention may be in any formsuitable for the intended method of administration, including, forexample, a solution, a suspension, or an emulsion. Liquid carriers aretypically used in preparing solutions, suspensions, and emulsions.Liquid carriers contemplated for use in the practice of the presentinvention include, for example, water, saline, pharmaceuticallyacceptable organic solvent(s), pharmaceutically acceptable oils or fats,and the like, as well as mixtures of two or more thereof. The liquidcarrier may contain other suitable pharmaceutically acceptable additivessuch as solubilizers, emulsifiers, nutrients, buffers, preservatives,suspending agents, thickening agents, viscosity regulators, stabilizers,and the like. Suitable organic solvents include, for example, monohydricalcohols, such as ethanol, and polyhydric alcohols, such as glycols.Suitable oils include, for example, soybean oil, coconut oil, olive oil,safflower oil, cottonseed oil, and the like. For parenteraladministration, the carrier can also be an oily ester such as ethyloleate, isopropyl myristate, and the like. Compositions of the presentinvention may also be in the form of microparticles, microcapsules,liposomal encapsulates, and the like, as well as combinations of any twoor more thereof.

[0135] The compounds of the present invention may be administeredorally, parenterally, sublingually, by inhalation spray, rectally,vaginally, or topically in dosage unit formulations containingconventional nontoxic pharmaceutically acceptable carriers, adjuvants,and vehicles as desired. Topical administration may also involve the useof transdermal administration such as transdermal patches orionophoresis devices. The term parenteral as used herein includessubcutaneous injections, intravenous, intramuscular, intrasternalinjection, or infusion techniques.

[0136] Injectable preparations, for example, sterile injectable aqueousor oleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-propanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can beuseful in the preparation of injectables.

[0137] Suppositories for rectal or vaginal administration of the drugcan be prepared by mixing the drug with a suitable nonirritatingexcipient such as cocoa butter and polyethylene glycols that are solidat ordinary temperatures but liquid At the rectal temperature and willtherefore melt in the rectum and release the drug.

[0138] Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as isnormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

[0139] Liquid dosage forms for oral administration may includepharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art, such aswater. Such compositions may also comprise adjuvants, such as wettingagents, emulsifying and suspending agents, cyclodextrins, andsweetening, flavoring, and perfuming agents.

[0140] The compounds of the present invention can also be administeredin the form of liposomes. As is known in the art, liposomes aregenerally derived from phospholipids or other lipid substances.Liposomes are formed by mono- or multilamellar hydrated liquid crystalsthat are dispersed in an aqueous medium. Any non-toxic, physiologicallyacceptable and metabolizable lipid capable of forming liposomes can beused. The present compositions in liposome form can contain, in additionto a compound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andphosphatidyl cholines (lecithins), both natural and synthetic. Methodsto form liposomes are known in the art (Prescott 1976).

[0141] While the compounds of the invention can be administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more other compound as described herein, and/or incombination with other agents used in the treatment and/or prevention ofestrogen receptor-mediated disorders. Alternatively, the compounds ofthe present invention can be administered sequentially with one or moresuch agents to provide sustained therapeutic and prophylactic effects.Suitable agents include, but are not limited to, other SERMs as well astraditional estrogen agonists and antagonists. Representative agentsuseful in combination with the compounds of the invention for thetreatment of estrogen receptor-mediated disorders include, for example,tamoxifen, 4-hydroxytamoxifen, raloxifene, toremifene, droloxifene,TAT-59, idoxifene, RU 58,688, EM 139, ICI 164,384, ICI 182,780,clomiphene, MER-25, DES, nafoxidene, CP-336,156, GW5638, LY139481,LY353581, zuclomiphene, enclomiphene, ethamoxytriphetol, delmadinoneacetate, bisphosphonate, and the like. Other agents that can be combinedwith one or more of the compounds of the invention include aromataseinhibitors such as, but not limited to, 4-hydroxyandrostenedione,plomestane, exemestane, aminogluethimide, rogletimide, fadrozole,vorozole, letrozole, and anastrozole.

[0142] Still other agents useful for combination with the compounds ofthe invention include, but are not limited to antineoplastic agents,such as alkylating agents. Other classes of relevant antineoplasticagents include antibiotics, hormonal antineoplastics andantimetabolites. Examples of useful alkylating agents include alkylsulfonates such as busulfan, improsulfan and piposulfan; aziridines,such as a benzodizepa, carboquone, meturedepa and uredepa; ethyleniminesand methylmelamines such as altretamine, triethylenemelamine,triethylenephosphoramide, triethylenethiophosphoramide andtrimethylolmelamine; nitrogen mustards such as chlorambucil,chlornaphazine, cyclophosphamide, estramustine, iphosphamide,mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,novembichine, phenesterine, prednimustine, trofosfamide, and uracilmustard; nitroso ureas, such as carmustine, chlorozotocin, fotemustine,lomustine, nimustine, ranimustine, dacarbazine, mannomustine,mitobronitol, mitolactol and pipobroman. More such agents will be knownto those having skill in the medicinal chemistry and oncology arts.

[0143] Additional agents suitable for combination with the compounds ofthe present invention include protein synthesis inhibitors such asabrin, aurintricarboxylic acid, chloramphenicol, colicin E3,cycloheximide, diphtheria toxin, edeine A, emetine, erythromycin,ethionine, fluoride, 5-fluorotryptophan, fusidic acid, guanylylmethylene diphosphonate and guanylyl imidodiphosphate, kanamycin,kasugamycin, kirromycin, and O-methyl threonine, modeccin, neomycin,norvaline, pactamycin, paromomycine, puromycin, ricin, α-sarcin, shigatoxin, showdomycin, sparsomycin, spectinomycin, streptomycin,tetracycline, thiostrepton and trimethoprim. Inhibitors of DNAsynthesis, including alkylating agents such as dimethyl sulfate,mitomycin C, nitrogen and sulfur mustards, MNNG and NMS; intercalatingagents such as acridine dyes, actinomycins, adriamycin, anthracenes,benzopyrene, ethidium bromide, propidium diiodide-intertwining, andagents such as distamycin and netropsin, can also be combined withcompounds of the present invention in pharmaceutical compositions. DNAbase analogs such as acyclovir, adenine, β-1-D-arabinoside,arnethopterin, aminopterin, 2-aminopurine, aphidicolin, 8-azaguanine,azaserine, 6-azauracil, 2′-azido-2′-deoxynucleosides,5-bromodeoxycytidine, cytosine, β-1-D-arabinoside, diazooxynorleucine,dideoxynucleosides, 5-fluorodeoxycytidine, 5-fluorodeoxyuridine,5-fluorouracil, hydroxyurea and 6-mercaptopurine also can be used incombination therapies with the compounds of the invention. Topoisomeraseinhibitors, such as coumermycin, nalidixic acid, novobiocin and oxolinicacid, inhibitors of cell division, including colcemide, colchicine,vinblastine and vincristine; and RNA synthesis inhibitors includingactinomycin D, α-amanitine and other fungal amatoxins, cordycepin(3′-deoxyadenosine), dichlororibofuranosyl benzimidazole, rifampicine,streptovaricin and streptolydigin also can be combined with thecompounds of the invention to provide pharmaceutical compositions. Stillmore such agents will be known to those having skill in the medicinalchemistry and oncology arts.

[0144] In addition, the compounds of the present invention can be used,either singly or in combination as described above, in combination withother modalities for preventing or treating estrogen receptor-mediateddiseases or disorders. Such other treatment modalities include withoutlimitation, surgery, radiation, hormone supplementation, and dietregulation. These can be performed sequentially (e.g., treatment with acompound of the invention following surgery or radiation) or incombination (e.g., in addition to a diet regimen).

[0145] In another embodiment, the present invention includes compoundsand compositions in which a compound of the invention is either combinedwith, or covalently bound to, a cytotoxic agent bound to a targetingagent, such as a monoclonal antibody (e.g., a murine or humanizedmonoclonal antibody). It will be appreciated that the latter combinationmay allow the introduction of cytotoxic agents into cancer cells withgreater specificity. Thus, the active form of the cytotoxic agent (i.e.,the free form) will be present only in cells targeted by the antibody.Of course, the compounds of the invention may also be combined withmonoclonal antibodies that have therapeutic activity against cancer.

[0146] The additional active agents may generally be employed intherapeutic amounts as indicated in the PHYSICIANS' DESK REFERENCE (PDR)53rd Edition (1999), which is incorporated herein by reference, or suchtherapeutically useful amounts as would be known to one of ordinaryskill in the art. The compounds of the invention and the othertherapeutically active agents can be administered at the recommendedmaximum clinical dosage or at lower doses. Dosage levels of the activecompounds in the compositions of the invention may be varied to obtain adesired therapeutic response depending on the route of administration,severity of the disease and the response of the patient. The combinationcan be administered as separate compositions or as a single dosage formcontaining both agents. When administered as a combination, thetherapeutic agents can be formulated as separate compositions that aregiven at the same time or different times, or the therapeutic agents canbe given as a single composition.

[0147] 4.6 Treatment of Estrogen Receptor-Mediated Disorders

[0148] In accordance with yet other embodiments, the present inventionprovides methods for treating or preventing an estrogenreceptor-mediated disorder in a human or animal subject in which anamount of an estrogen receptor-modulating compound of the invention thatis effective to modulate estrogen receptor activity in the subject.Other embodiments provided methods for treating a cell or a estrogenreceptor-mediated disorder in a human or animal subject, comprisingadministering to the cell or to the human or animal subject an amount ofa compound or composition of the invention effective to modulateestrogen receptor activity in the cell or subject. Preferably, thesubject will be a human or non-human animal subject. Modulation ofestrogen receptor activity detectable suppression or up-regulation ofestrogen receptor activity either as compared to a control or ascompared to expected estrogen receptor activity.

[0149] Effective amounts of the compounds of the invention generallyinclude any amount sufficient to detectably modulate estrogen receptoractivity by any of the assays described herein, by other activity assaysknown to those having ordinary skill in the art, or by detectingprevention or alleviation of symptoms in a subject afflicted with aestrogen receptor-mediated disorder.

[0150] Estrogen receptor-mediated disorders that may be treated inaccordance with the invention include any biological or medical disorderin which estrogen receptor activity is implicated or in which theinhibition of estrogen receptor potentiates or retards signaling througha pathway that is characteristically defective in the disease to betreated. The condition or disorder may either be caused or characterizedby abnormal estrogen receptor activity. Representative estrogenreceptor-mediated disorders include, for example, osteoporosis,atheroschlerosis, estrogen-mediated cancers (e.g., breast andendometrial cancer), Turner's syndrome, benign prostate hyperplasia(ie., prostate enlargement), prostate cancer, elevated cholesterol,restenosis, endometriosis, uterine fribroid disease, skin and/or vaginaatrophy, and Alzheimer's disease. Successful treatment of a subject inaccordance with the invention may result in the prevention, inducementof a reduction in, or alleviation of symptoms in a subject afflictedwith an estrogen receptor-mediated medical or biological disorder. Thus,for example, treatment can result in a reduction in breast orendometrial tumors and/or various clinical markers associated with suchcancers. Likewise, treatment of Alzheimer's disease can result in areduction in rate of disease progression, detected, for example, bymeasuring a reduction in the rate of increase of dementia.

[0151] The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. It willbe understood, however, that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination, and the severity of the particular diseaseundergoing therapy. The prophylactically or therapeutically effectiveamount for a given situation can be readily determined by routineexperimentation and is within the skill and judgment of the ordinaryclinician.

[0152] For exemplary purposes of the present invention, aprophylactically or therapeutically effective dose will generally befrom about 0.1 mg/kg/day to about 100 mg/kg/day, preferably from about 1mg/kg/day to about 20 mg/kg/day, and most preferably from about 2mg/kg/day to about 10 mg/kg/day of a estrogen receptor-modulatingcompound of the present invention, which may be administered in one ormultiple doses.

5 Examples

[0153] The following Examples are provided to illustrate certain aspectsof the present invention and to aid those of skill in the art in the artin practicing the invention. These Examples are in no way to beconsidered to limit the scope of the invention in any manner.

[0154] 5.1 Preparation of Compounds of the Invention

[0155] 5.1.1 General Procedures

[0156] All reactions were carried out under nitrogen or argonatmosphere. All reagents obtained from commercial sources were usedwithout further purification. Anhydrous solvents were obtained fromcommercial sources and used without further drying. Separation andpurification of the products were carried out using any or combinationof the following methods. Flash column chromatography was performed withsilica gel, 200-400 mesh, 60 A (Aldrich Chemical Company, Inc.,Milwaukee, WI) or a Flash 40 chromatography system and KP-Sil, 60 A(Biotage, Charlottesville, Virginia). Typical solvents employed weredichloromethane (DCM), methanol (MeOH), ethyl acetate (EtOAc), andhexane (Hex). Preparative TLC was conducted using 20×20 cm plates coatedwith Merch-EM Type-60, GF-254 silica gel. Preparative HPLC was performedwith Dynamax System using a C-18 reversed phase column (Ranin).Compounds of the present invention were characterized by LC/MS usingeither Waters Micromass Platform LCZ system (ionization mode: electronspray positive; column: HP-Eclipse XDB-C18, 2 x 50 mm, buffer A: H₂0with 0.1 % trifluoroacetic acid (TFA), buffer B: acetonitrile (MeCN)with 0.1% TFA, elution gradient: 5-95% buffer over 5 minute period, flowrate: 0.8 mL/min) or HP 1100 Series LC/MSD system (ionization mode:electron spray positive; column: HP-Eclipse XDB-C18, 2×50 mm, buffer A:H₂O with 0.1% TFA, buffer B: MeCN with 0.1% TFA, elution gradient: 5-95%buffer over 3.5 to 6 minute period, flow rate: 0.8 to 0.4 mL/min).Purity of the compounds was also evaluated by HPLC using a WatersMillennium chromatography system with a 2690 Separation Module (Milford,Massachusetts). The analytical columns were Alltima C- 18 reversedphase, 4.6×250 mm from Alltech (Deerfield, Illinois). A gradient elutionwas used, typically starting with 5% MeCN/ 95% water and progressing to100% MeCN over a period of 40 minuets. All solvents contained 0.1% TFA.Compounds were detected by ultraviolet light (Uv) absorption at 214 run.Some of the mass spectrometric analysis was performed on a FisonsElectrospray Mass Spectrometer. All masses are reported as those of theprotonated parent ions unless otherwise noted. Nuclear magneticresonance (NMR) analysis was performed with a Varian 300 MHz NMR (PaloAlto, California). The spectral reference was either TMS or the knownchemical shift of the solvent. Proton NMR (′H NMR) data are reported asfollows: chemical shift (8) in ppm, multiplicity (s=singlet, d=doublet,t =triplet, q=quartet, p=pentet, m=multiplet, dd=doublet of doublet,br=broad), coupling constant (Hz), integration and assignment. Meltingpoints were determined on a Laboratory Devices MEL-TEMP apparatus(Holliston, Massachusetts) and are reported uncorrected. Compound nameswere generated using NOMENCLATOR (Chemlnnovation Software, Inc., SanDiego, CA).

[0157] 5.1.2 Synthesis of Estrogen Receptor-Modulating Pyrazoles

[0158] 5.1.2.1 Synthesis of4-15-(diphenyimethyl)-4-ethyl-1-methylpyrazol-3-yllphenof

[0159] This compound was synthesized based upon Scheme 1.

[0160] Step 1: To a solution of 4′-methoxybutyrylphenone (1.0 equiv.) inTHF at -78° C. was added dropwise 1.5 equiv. of [(CH₃)₂Si]₂NLi. Thesolution was stirred for I h at -78° C., followed by addition of 1.2equiv. of 2,2-diphenylacetyl chloride. The reaction mixture was stirredfor 10 min at -78° C. and then for 22 h at rt, acidified with 10% citricacid, and extracted with EtOAc. The combined organic layers were washedwith water and dried over Na₂SO₄. Removal of solvent in vacuo provided acrude solid which was purified by flash chromatography (CH₂CI₂) to giveproduct 2-ethyl- I-(4-methoxyphenyl)-4,4diphenylbutane-1,3-dione.

[0161] Step 2: A mixture of the 1,3-diketone obtained in step I (1.0equiv.), methyl hydrazine (1.5 equiv.), conc. HCI aq. (catalytic amount)and ethanol was heated to reflux overnight. Cooled to rt and removedsolvent in vacuo. Water and ethyl acetate were added. The organic layerwas separated, washed with dil. HCI, brine, dried, filtered and thesolvent was concentrated in vacuo to give the pyrazole product.

[0162] Step 3: Demethylation was performed using as described in Scheme1 to afford the fmal product. ESMS m/z 369 (MH+), C₂₅H₂₄N₂0 368 g/mol,HPLC purity =85% 5.1.2.2 Synthesis of 4-!4-ethylI1-methyl-5-(2-phenylethyl)pyrazol-3-ylphenol

[0163] This compound was synthesized in the same manner as described inSection 5.1.2. I. In step I, 3-phenylpropanoyl chloride and4′-methoxybutyrylphenone were used to form the 1 ,3-diketone.

[0164] ESMS m/z 307(Mh⁴), C₂₀H₂₂N₂O=306 g/mol, HPLC purity=64%.

[0165] 5.1.2.3 Synthesis of4-(4-ethyl-1-methyl-5(2-thienyl)pyrazol-3yl)phenol

[0166] This compound was synthesized in the same manner as described inSection 5.1.2.1. In step 1, thiophene-2-carbonyl chloride and4′-methoxybutyrylphenone were used to form the 1,3-diketone.

[0167] ESMS m/z 285 (MH⁺), C₁₆H₁₆N₂OS=284 g/mol, HPLC purity=98%

[0168] 5.1.2.4 Synthesis of4-[1-methyl-5-(2-phenylethyl)4-prop-2enypyrazol-3-yl]phenol

[0169] This compound was synthesized based upon Scheme 1 and Scheme 3.

[0170] Step 1: Formation of 1,3-diketone. Same as step 1 in described inSection 5.1.2.1 using 4′-methoxyacetophenone and 3-phenylpropanoylchloride as starting materials.

[0171] Step 2: Alkylation. A THF solution of the above 1,3-diketone (1.0equiv.) was added dropwise to a suspension of sodium hydride (1.1 eq) inTHF at 0° C. The mixture was stirred at rt for 30 min. followed byaddition of allylbromide (1.1 equiv.). The reaction mixture was stirredat rt overnight, poured into saturated NH₄CI aq. and extracted withether and DCM. The organic extracts were washed with brine, dried withMgSO₄ and concentrated in vacuo to give the product.

[0172] Step 3: Same as step 2 in Section 5.1.2.1

[0173] Step 4: Demethylation was performed as described in Scheme I toafford the final product.

[0174] ESMS m/z 319 (MH⁺), C21H₂₂N₂O=318 g/mol, HPLC purity=80%

[0175] 5.1.2.5 Synthesis of4-11-methyl-5(phenoxymethyl)4-prop-2-enypyrazol-3yl]phenol

[0176] This compound was synthesized in the same manner as described inSection 5.1.2.4. In step 1, 2-phenoxyacetyl chloride and4′-methoxyacetophenone were used to form the 1,3-diketone.

[0177] ESMS m/z 321 (MH⁺), C₂₀H₂₂N₂O₂=320 g/mol, HPLC purity=60%

[0178] 5.1.2.6 Synthesis of4-[3,5-bis(4-hydroxyphenyl)-1-methylpyrazol4-yl]phenol

[0179] This compound was synthesized based upon Scheme I.

[0180] Step 1: To a solution of desoxyanisoin (1.0 equiv.) in THF at-78° C. was added dropwise 1.5 equiv. of [(CH₃)₂Si]₂NLi. The solutionwas stirred for I h at -78° C., followed by addition of 1.2 equiv. ofp-anisoyl chloride. The reaction mixture was stirred for 10 min at -78°C. and then for 22 h at rt, acidified with 10% citric acid, andextracted with EtOAc. The combined organic layers were washed with waterand dried over Na₂SO₄. Removal of solvent in vacuo provided a crudesolid which was purified by flash chromatography (CH₂CI₂) to give1,2,3-tris(4-methoxyphenyl)propane- 1 ,3-dione.

[0181] Step 2: A mixture of the 1,3-diketone obtained in step I (1.0equiv.), methyl hydrazine (1.5 equiv.), conc. HCI aq. (catalytic amount)and ethanol was heated to reflux overnight. Cooled to rt and removedsolvent in vacuo. Water and ethyl acetate were added. The organic layerwas separated, washed with dil. HCI, brine, dried, filtered and thesolvent was concentrated in vacuo to give the product4-[4,5-bis(4-methoxyphenyl)1-methylpyrazol-3-yl]-1-methoxybenzene.

[0182] Step 3: Demethylation was performed using Method 1described inScheme 1 to afford the final product.

[0183] ESMS m/z 359 (MH⁺), C22H₁₈N₂O₃=358 g/mol, HPLC purity=90%.

[0184] 5.1.2.7 Synthesis of4-[3,5-bis(4-hydroxyphenyl)-l-phenylpyrazo(4-ylqphenof

[0185] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, phenyl hydrazine was used as the reagent toform pyrazole.

[0186] 5 ESMS m/z 421 (MH⁺), C₂₇H₂₀N₂O₃=420 g/mol, HPLC purity=90%.

[0187] 5.1.2.8 Synthesis of4-[i-(4-bromophenyl)-5-(4-hydroxyphenyl)4-benzypyrazol-3-ylqphenol

[0188] This compound was synthesized based upon Scheme 1.

[0189] Step 1: To a solution of I-(4-methoxyphenyl)-3-phenylpropan-1-one(1.0 equiv.) in THF at -78° C. was added dropwise 1.5 equiv. of[(CH₃)₂Si]₂NLi. The solution was stirred for 1 h at -78° C., followed byaddition of 1.2 equiv. of p-anisoy] chloride. The reaction mixture wasstirred for 10 min at -78° C. and then for 22 h at rt, acidified with10% citric acid, and extracted with EtOAc. The combined organic layerswere washed with water and dried over Na₂SO₄. Removal of solvent invacuo provided a crude solid which was purified by flash chromatography(CH₂CI₂) to give 1,3-bis(4-methoxyphenyl)2-benzylpropane-1,3-dione.

[0190] Step 2: A mixture of the 1,3-diketone obtained in step 1 (1.0equiv.), 4-bromophenyl hydrazine (1.5 equiv.), conc. HCI aq. (catalyticamount) and ethanol was heated to reflux overnight. Cooled to rt andremoved solvent in vacuo. Water and ethyl acetate were added. Theorganic layer was separated, washed with dil. HCI, brine, dried,filtered and the solvent was concentrated in vacuo to give the product1-[1-(4-bromophenyl)-3-(4-methoxyphenyl)-4-benzylpyrazol-5-yl]-4-methoxybenzene.

[0191] Step 3: Demethylation was performed as described in Scheme 1 toafford the final product.

[0192]¹H NMR (CDCI₃): ε3.86 (2H, s), 6.67 (2H, d, J=8.8Hz), 6.74 (2H, d,J=8.8Hz), 6.88 (2H, d, J=8.8Hz), 6.98 (2H, d, J=7.2Hz), 7.05-7.09 (1H,m), 7.14 (4H, d, J=8.8Hz), 7.36 (4H, d, J=8.8Hz); ESMS m/z 497/499(MH⁺), C₂₈H21,BrN₂O₂=496/498 g/mol (1Br); BPLC purity=85.%.

[0193] 5.1.2.9 Synthesis of4-[1-(4chloro-2-methylphenyl)-5(4-hydroxyphenyl)4-benzyfpyrazoi-3-yl]phenol

[0194] This compound was synthesized in the same manner as described inSection 5.1.2.8. In step 2, 4-chloro-2- methylphenyl hydrazine was usedto form the pyrazole. ¹H NMR (CDC1₃): δ2.02 (3H, s), 3.97 (2H, s), 6.60(2H, d, J=8.8Hz), 6.73 (2H, d, J=8.8Hz), 6.86 (2H, d, J=8.8Hz),7.08-7.19 (6H, m), 7.21-7.26 (2H, m), 7.46 (2H, d, J=8.8Hz); ESMS m/z467/469 (MH+), C₂₉H₂₃CIN₂O₂=466 g/mol; HPLC purity=81%.

[0195] 5.1.2.10 Synthesis of4-[1-(3-hlorophenyi)-5-(4-hydroxypheny)4-benzylpyrazol-3-yl]phenol

[0196] This compound was synthesized in the same manner as described inSection 5.1.2.8. In step 2, 3-chlorophenyl hydrazine was used to formthe pyrazole heterocycle. ¹H NMR (CDC1₃): δ3.95 (2H, s), 6.73 (2H, d,J=8.8Hz), 6.78(2H, d, J=8.8Hz), 6.98 (2H, d, J=9.2Hz), 7.05-7.18 (6H,m), 7.22(2H, d,J=7.1Hz), 7.46 (1H, t,J=2.1Hz), 7.51(2H, d, J=8.8Hz);ESMS m/z453/455(MH+), C₂₈H₂₁CIN₂O₂=452 g/mol; HPLC purity=89%.

[0197] 5.1.2.11 Synthesis of4-[1-(4chloropheny)-5-(4-hydroxyphenyl)-4-benzylpyrazol-3-yl]phenol

[0198] This compound was synthesized in the same manner as described inSection 5.1.2.8. In step 2, 4-chlorophenyl hydrazine was used to formthe pyrazole heterocycle. ¹H NMR (CDC1₃): δ3.97 (2H, s), 6.59 (2H, d,J=8.8Hz), 6.73 (2H, d, J=8.8Hz), 6.94 (2H, d, J=8.8Hz), 7.11-7.18 (4H,m), 7.24-7.27(3H, m), 7.34 (1H, dd, J=7.8, 3.5Hz), 7.44 (1H,dd,J=6.8,3.9Hz), 7.48 (2H, d, J=8.8Hz); ESMS m/z 453/455 (MH+),C₂₈H₂₁CIN₂O₂=452 g/mol; HPLC purity=86%.

[0199] 5.1.2.12 Synthesis of4-[3,4-bis(4-hydroxyphenyl)-1-(2-methylphenyl)pyrazol-5-y]phenolhydrazine was used as the reagent to form pyraole.

[0200] ESMS m/z 439 (M⁺), C₂₇H₁₉FN₂O₃=438 g/mol, HPLC purity=90%.

[0201] 5.1.2.14 Synthesis of4-[3,4-bis(4-hydroxyphenyl)-1l-(2ethylphenyI)pyrazol-5Aphenol hydrazinewas used as the reagent to form pyrazole.

[0202] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 2-methylphenyl hydrazine was used as thereagent to form pyrazole.

[0203] ESMS m/z 449 (MH⁺), C₂₉H₂₄N₂O₃=448 g/mol, HPLC purity=90%.

[0204] 5.1.2.15 Synthesis of4-[3,5-bis(4-hydroxyphenyl)-1-(4-fluorophenyl)pyrazol-4-yl]phenol

[0205] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 4-fluorophenyl hydrazine was used as thereagent to form pyrazole.

[0206] ESMS m/z 439 (MH⁺), C₂₇H₁₉FN₂O₃=438 g/mol, HPLC purity=90%.

[0207] 5.1.2.16 Synthesis of4-[1-(2,4-difluorophenyl)-3,4-bis(4-hydroxyphenyl)pyrazol-5-yl]phenol

[0208] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 2,4-difluorophenyl hydrazine was used as thereagent to form pyrazole.

[0209] ESMS m/z 457 (MH⁺), C₂₇H₁₈F₂N₂O₃=456 g/mol, HPLC purity=90%.

[0210] 5.1.2.17 Synthesis of4-13,4-bis(4-hydroxyphenyl)-I-[2-(trifluoromethyl)phenyl]pyrazol-5-yllphenol

[0211] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 2- trifluoromethylphenyl hydrazine was usedas the reagent to form pyrazole.

[0212] ESMS m/z 489 (MH⁺), C₂₈H₁₉F₃N₂O=488 g/mol, HPLC purity=85%.

[0213] 5.1.2.18 Synthesis of4-[3,4-bis(4-hydroxyphenyl)-1-(2-fluorophenyl)pyrazol-5-yl]phenol

[0214] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 2-fluorophenyl hydrazine was used as thereagent to form pyrazole.

[0215] ESMS m/z 439(MH⁺), C₂₇H₁₉FN₂O₃=438 g/mol, HPLC purity=80%.

[0216] 5.1.2.19 Synthesis of4-[3,4-bis(4-hydroxyphenyl)-1-(3-methylphenyl)pyrazol-5-yl]phenol

[0217] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 3-methylphenyl hydrazine was used as thereagent to form pyrazole.

[0218] ESMS m/z 435 (MH⁺), C₂₈H₂₂N₂O₃=434 g/mol, HPLC purity=80%.

[0219] 5.1.2.20 Synthesis of4-[3,4-bis(4-hydroxyphenyl)-1-(4chloro-2-methylphenyl)pyrazol-5-yl]phenoi

[0220] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 4-chloro-2- methylphenyl hydrazine was usedas the reagent to form pyrazole.

[0221] ESMS m/z 469 (MH⁺), C₂₈H₂₁ CIN₂O₃=468 g/mol, HPLC purity=80%.

[0222] 5.1.2.21 Synthesis of4-[3,5-bis(4-hydroxyphenyl)-1-(4-methylphenyl)pyrazolA-yl]phenol

[0223] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 4-methylphenyl hydrazine was used as thereagent to form pyrazole.

[0224] ESMS m/z 435 (MH⁺), C₂₈H₂₂N₂O₃=434 g/mol, HPLC purity=80%.

[0225] 5 5.1.2.22 Synthesis of4-[1-(2,3-dichlorophenyl)-3,4-bis(4-hydroxyphenyl)pyrazol-5-yllphenol

[0226] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 2,3-dichlorophenyl hydrazine was used as thereagent to form pyrazole.

[0227] ESMS m/z 489 (MH⁺), C₂₇H₁₈C1₂N₂O₃=490 g/mol, HPLC purity=80%

[0228] 5.1.2.23 Synthesis of4-[3,4-bis(4-hydroxyphenyl)-1-(5fluoro-2-methylphenyl)pyrazol-5-yl]phenol

[0229] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 5-fluoro-2- methylphenyl hydrazine was usedas the reagent to form pyrazole.

[0230] ESMS m/z 453 (MH⁺), C₂₈H₂₁FN₂O₃=452 g/mol, HPLC purity=low

[0231] 5.1.2.24 Synthesis of4-[3,4-bis(4-hydroxyphenyl)-1-(2-chlorophenyl)pyrazol-5-yl]phenol

[0232] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 2-chlorophenyl hydrazine was used as thereagent to form pyrazole.

[0233] ESMS m/z 455 (MH⁺), C₂₇H₁₉CIN₂O₃=454 g/mol, HPLC purity=80%

[0234] 5.1.2.25 Synthesis of4q3,4-bis(4-hydroxyphenyi)-1-[4-(tert-butyl)phenyl]pyrazol-5-yl}phenol

[0235] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 4-t-butylphenyl hydrazine was used as thereagent to form pyrazole.

[0236] ESMS m/z 477 (MH⁺), C₃₁H₂₈N₂O₃=476 g/mol, HPLC purity=80%.

[0237] 5.1.2.26 Synthesis of4-[3,4-bis(4-hydroxyphenyi)-1-(3lorophenyl)pyrazol-5-yl]phenol

[0238] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 3-chlorophenyl hydrazine was used as thereagent to form pyrazole.

[0239] ESMS m/z 455 (MH⁺), C₂₇H₁₉CIN₂O₃=454 g/mol, HPLC purity=80%.

[0240] 5.1.2.27 Synthesis of4-[1-(2,4-dichlorophenyl)-3,4-bis(4-hydroxyphenyl)pyrazol-5-yl]phenol

[0241] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 2,4-dichlorophenyl hydrazine was used as thereagent to form pyrazole.

[0242] ESMS m/z 490 (MH⁺), C₂₇H₁₈C1₂N₂O₃=489 g/mol, HPLC purity=80%.

[0243] 5 5.1.2.28 Synthesis of4-3,5-bis(4-hydroxyphenyi)-1-(4chlorophenyl)pyrazolyq]phenol

[0244] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 4-chlorophenyl hydrazine was used as thereagent to form pyrazole.

[0245] ESMS m/z 455 (MH⁺), C₂₇H₁₉CIN₂O₃=454 g/mol, HPLC purity=80%.

[0246] 5.1.2.29 Synthesis of4-[1-(2,6-dichlorophenyi)-3,4-bis(4-hydroxyphenyl)pyrazol-5-y]phenol

[0247] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 2,6-dichlorophenyl hydrazine was used as thereagent to form pyrazole.

[0248] ESMS m/z 490 (MH⁺), C₂₇H₁₈C1₂N₂O₃=489 g/mol, HPLC purity =60%.

[0249] 5.1.2.30 Synthesis of4-[3,4-bis(4-hydroxyphenyl)-i-(2,3-dimethylphenyl)pyrazol-5-yl]phenol

[0250] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 2,3-dimethylphenyl hydrazine was used as thereagent to form pyrazole.

[0251] ESMS m/z 449 (MH⁺), C₂₈H₁₉F₃N₂O₄=448 g/mol, HPLC purity=85%.

[0252] 5.1.2.31 Synthesis of4-[3,4-bis(4-hydroxyphenyl)-1-(3hIoro-4-fluorophenyf)pyrazol-5-y]phenol

[0253] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 3-chloro-4- fluorophenyl hydrazine was usedas the reagent to form pyrazole.

[0254] ESMS m/z 473 (MH⁺), C₂₇H₁₈CIFN₂O₃=472 g/mol, HPLC purity=80%.

[0255] 5.1.2.32 Synthesis of4i3,4-bis(4-hydroxyphenyl)-1-[4-(trifluoromethoxy)phenyl]pyrazol-5-yl}phenol

[0256] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 4-trifluoromethoxyphenyl hydrazine was usedas the reagent to form pyrazole.

[0257] ESMS m/z 505 (MH+), C₂sHl₉F₃N₂0₄=504 g/mol, HPLC purity=85%.

[0258]5.1.2.33 Synthesis of443,4-bis(4-hydroxypheny)-l-[4-(bifluorometho)pheny]pyrazol-5-ylphenol

[0259] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 4-trifluoromethylphenyl hydrazine was usedas the reagent to form pyrazole.

[0260] ESMS m/z 489 (MH⁺), C₂₈H₁₉F₃N₂O₃=488 g/mol, HPLC purity=80%.

[0261] 5.1.2.34 Synthesis of4-[3,5-bis(4-hydroxypheny)-1-(4-iodophenyl)pyrazol-4-y]phenol

[0262] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 4-iodophenyl hydrazine was used as thereagent to form pyrazole.

[0263] ESMS m/z 547 (MH⁺), C₂₇H₁₉IN₂O₃=546 g/mol, HPLC purity=70%.

[0264] 5.1.2.35 Synthesis of4-(3,4-bis(4-hydroxyphenyl)-I-[2-chloro-5-(bifluoromethyl)phenyl]pyrazol-5-ylphenol

[0265] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 2-chloro-5-trifluoromethylphenyl hydrazinewas used as the reagent to form pyrazole.

[0266] ESMS m/z 523 (MH⁺), C₂₈H₁₈CIF₃N₂O₃=522 g/mol, HPLC purity=65%.

[0267] 5.1.2.36 Synthesis of4-[3,4-bis(4-hydroxyphenyl)-1-(1,3-dimethyl-5-nitropyrazol4-yl)pyrazol-5-yllphenol

[0268] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 1,3-dimethyl-5- nitropyrazole-4-ylhydrazinewas used as the reagent to form pyrazole.

[0269] ESMS m/z 484 (MH⁺), C₂₆H₂₁N₅O₅=483 gtmol, HPLC purity=60%.

[0270]5.1.2.37 Synthesis of443,4-bis(4-hydroxyphenyl)-l-[5-chloro-3-(bifluoromethyl)(2-pyddyl)]pyrazol-5-yllphenol

[0271] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 5-chloro-3-trifluoromethyl-2-pyridylhydrazine was used as the reagent to formpyrazole.

[0272] ESMS m/z 524 (MH⁺), C₂₇H₁₇CIF₃N₃O₃=523 g/mol, HPLC purity=80%.

[0273]5.1.2.38 Synthesis of4-[3,4-bis(4-hydroxyphenyl)-1-(1,4-dimethylpyrazolo[4,5-e]pyridin-6-yl)pyrazol-5yl]phenol

[0274] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 1,4-dimethylpyrazolo[5,4-b]pyridine-6-ylhydrazine was used as the reagent toform pyrazole.

[0275] ESMS m/z 504 (MH⁺), C₃₀H₂₅N₅O₃=503 g/mol, HPLC purity=85%.

[0276] 5.1.2.39 Synthesis of4-[3,5-bis(4-hydroxyphenyl)-1-(6-methylpyridazin-3-yl)pyrazol-yl]phenol

[0277] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 6-methylpyridazine-3-ylhydrazine was used asthe reagent to form pyrazole.

[0278] ESMS m/z 437 (MH⁺), C₂₆H₂₀N₄O₃=436 g/mol, HPLC purity=70%.

[0279] 5.1.2.40 Synthesis of4-[3,4-bis(4-hydroxyphenyl)-1-(6chloro-2-fluorophenyl)pyrazol-5-yl]phenol

[0280] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 6-chloro-2-fluorophenyl hydrazine was usedas the reagent to form pyrazole.

[0281] ESMS m/z 473 (MH⁺), C₂₇H₁₈ClFN₂O₃=472 g/mol, HPLC purity=85%.

[0282]4-[1-(2-fluorophenyl)-5-(4-methylphenyl)-4-benzylpyrazol-3-yl]phenol

[0283] This compound was synthesized in the same manner described inSection 5.1.2.8. In step 2, 2-fluorophenyl hydrazine was used to formthe pyrazole heterocycle.

[0284]¹H NMR (CDCl₃): δ4.11 (2H, s), 6.80 (2H, d, J=8.5Hz), 6.93 (2H, d,J=8.5Hz), 7.09 (2H, d, J=8.5 Hz), 7.19-7.24 (1H, m), 7.23 (2H, d, J=8.5Hz), 7.27-7.32 (1H, m), 7.35 (1H, d, J=8.3 Hz), 7.38 (IH, d, J=8.3Hz),7.46-7.52 (1H, m), 7.55 (2H, d, J=8.3 Hz), 7.62 (1H, td, J=8.3, 1.6 Hz),7.66 (1H, s); ESMS m/z 437 (MH⁺), C₂₈H₂₁FN₂O₂=436 g/mol; HPLCpurity=79%.

[0285] 5.1.2.41 Synthesis of3-{[3,5-bis(4-hydroxypheny)-4-benzylpyrazolyl]methyl}phenol

[0286] This compound was synthesized based upon Scheme 4.

[0287] Step 1: To a solution of 1-(4-methoxyphenyl)-3-phenylpropan-1-one(1.0 equiv.) in THF at −78° C. was added dropwise 1.5 equiv. of[(CH₃)₂Si]₂NLi. The solution was stirred for I h at -78° C., followed byaddition of 1.2 equiv. of p-anisoyl chloride. The reaction mixture wasstirred for 10 min at -78° C. and then for 22 h at rt, acidified with10% citric acid, and extracted with EtOAc. The combined organic layerswere washed with water and dried over Na₂SO₄. Removal of solvent invacuo provided a crude solid which was purified by flash chromatography(CH₂Cl₂) to give 1,3-bis(4-methoxyphenyl)-2-benzylpropane-1,3-dione.

[0288] Step 2: A mixture of the 1,3-diketone obtained in step 1 (1.0equiv.), hydrazine (3.0 equiv.), conc. HCl aq. (catalytic amount) andethanol was heated to reflux overnight. Cooled to rt and removed solventin vacuo. Water and ethyl acetate were added. The organic layer wasseparated, washed with dil. HCI, brine, dried, filtered and the solventwas concentrated in vacuo to give the product4-methoxy-1-[5-(4-methoxyphenyl)-4-benzylpyrazol-3-yl]benzene.

[0289] Step 3: Alkylation. Pyrazole obtained from the above step wasdissolved in DMF. Cesium carbonate (6 equiv.) and 3′-methoxybenzylbromide (4 equiv.) were added to the solution and the reaction wasallowed to proceed at 90° C. for 3 days. EtOAc was added and thesolution was washed with 10% citric acid (2×20 mL), 10% NaHCO₃ andbrine. The organic layer was concentrated under reduced pressure and theresulting residue was taken up in 90% MeCN/H₂O and lyophilized.Purification was achieved by flash chromatography (EtOAc/petrol).

[0290] Step 4: Demethylation was performed as described in Scheme 1 toafford the final product.

[0291]¹H NMR (CDCl₃): δ3.72 (2H, s), 5.05 (2H, s), 6.37 (1H, d, J=7.6Hz), 6.46 (1H, s), 6.58 (1H, d, J=7.6 Hz), 6.65 (2H, d, J=7.6 Hz), 6.67(2H, d, J=7.6 Hz), 6.87 (4H, d, J=7.8 Hz), 6.95-7.11 (4H, m), 7.26 (2H,d, JV7.8 Hz); ESMS nvz 449 (MH+), C₂₉H₂₄N₂O₃=448 g/mol; HPLC purity=85%.

[0292] 5.1.2.42 Synthesis of1-[3,5-bis(4-hydroxyphenyl)-4-benzylpyrazolyl]-4-(methylsulfonyl)benzene

[0293] This compound was synthesized in the same manner described inSection 5.1.2.8. In step 2, 4-methanesulfonylphenyl hydrazine was usedto form the pyrazole heterocycle.

[0294]¹H NMR (CDCl₃): δ2.89 (3H, s), 3.74 (2H, s), 6.59 (2H, d, J=8.6Hz), 6.63 (2H, d, J=8.6 Hz), 6.79 (2H, d, J=8.6 Hz), 6.87 (2H, d, J=7.5Hz), 6.96 (1H, t, J=6.8 Hz), 7.03 (2H, t, 3-7.2 Hz), 7.28 (2H, d, J=8.6Hz), 7.36 (2H, d, J=8.6 Hz), 7.65 (2H, d, J=8.6 Hz).; ESMS m/z 497(MH+), C₂₉H₂₄N₂O4S=496 g/mol; HPLC purity 79%.

[0295] 5.1.2.43 Synthesis of4-[5-(4-hydroxyphenyl)-1-(2,3,4,5,6-pentafluorophenyl)4-benzylpyrazol-3-yl]phenol

[0296] This compound was synthesized in the same manner described inSection 5.1.2.8. In step 2, 1,2,3,4,5-pentafluorophenyl hydrazine wasused to form the pyrazole heterocycle.

[0297]¹H NMR (CDCl₃): δ3.94 (2H, s), 6.69 (2H, d, J=8.8 Hz), 6.76 (2H,d, J=8.8 Hz), 6.99 (2H, d, J=7.9 Hz), 7.06 (2H, d, J=7.2 Hz), 7.09 (2H,d,3J=8.8 Hz), 7.16 (1H, t, J=7.2 Hz), 7.45 (2H, d, J=8.8 Hz); ESMS ?/Wz509 (MH+), C₂₈H₁₇F₅N₂O₂=508 g/mol; HPLC purity=83%.

[0298] 5.1.2.44 Synthesis of'4-*5-(4-hydroxyphenyl)-4-benzyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl}phenol

[0299] This compound was synthesized in the same manner described inSection 5.1.2.8. In step 2,4-trifluoromethoxyphenyl hydrazine was usedto form the pyrazole heterocycle.

[0300]¹H NMR (CDCl₃): δ3.92 (2H, s), 6.71 (2H, d, J=8.8 Hz), 6.76 (2H,d, J=8.8 Hz), 6.96 (2H, d, J=8.1 Hz), 7.06 (2H, d, J=7.3 Hz), 7.09 (2H,d, J=8.8 Hz), 7.14 (1H, t, J=7.3 Hz), 7.20 (2H, d, J=8.1 Hz), 7.33 (2H,d, J=8.8 Hz), 7.49 (2H, d, J=8.8 Hz); ESMS m/z 503 (MH+),C₂₉H₂₁F₃N₂O₃=502 g/mol; HPLC purity=93%.

[0301] 5.1.2.45 Synthesis of4-[3,5bis(4-hydroxyphenyl)-1-(2-pyridyl)pyrazol-4-yl]phenol

[0302] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2,2-pyridylhydrazine was used as the reagent toform pyrazole.

[0303] ESMS m/z 422 (MH⁺), C₂₆H₁₉N₃O₃=421 g/mol, HPLC purity=90%.

[0304] 5.1.2.46 Synthesis of4-[1-(2,4dimethylphenyl)-4-ethyl-5-(4-hydroxypheny)pyrazol-3-yl]phenol

[0305] This compound was synthesized based upon Scheme 1.

[0306] Step 1: To a solution of 4′-methoxybutyrylphenone (1.0 equiv.) inTHF at −78° C. was added dropwise 1.5 equiv. of [(CH₃)₂Si]₂NLi. Thesolution was stirred for 1 h at −78° C., followed by addition of 1.2equiv. of p-anisoyl chloride. The reaction mixture was stirred for 10min at −78° C. and then for 22 h at rt, acidified with 10% citric acid,and extracted with EtOAc. The combined organic layers were washed withwater and dried over Na₂SO₄. Removal of solvent in vacuo provided acrude solid which was purified by flash chromatography (CH₂Cl₂) to give1,3-bis(4-methoxyphenyl)-2-ethylpropane-1,3-dione.

[0307] Step 2: A mixture of the 1,3-diketone obtained in step 1 (1.0equiv.), 2,4-ditnethylphenyl hydrazine (1.5 equiv.), conc. HCl aq.(catalytic amount) and ethanol was heated to reflux overnight. Cooled tort and removed solvent in vacuo. Water and ethyl acetate were added. Theorganic layer was separated, washed with dil. HCl, brine, dried,filtered and the solvent was concentrated in vacuo to give the product.

[0308] Step 3: Demethylation was performed as described in Scheme 1 toafford the final product.

[0309] ESMS m/z 385 (MH), C₂₅H₂₄N₂O₂ =384 g/mol, HPLC purity=80%.

[0310] 5.1.2.47 Synthesis of4-[4-ethyl-5-(4-hydroxyphenyl)-1-(3-methylphenyl)pyrazol-3-yl]phenol

[0311] This compound was synthesized in the same manner as described inSection 5.1.2.46. In step 2, 3-methylphenyl hydrazine was used as thereagent to form pyrazole.

[0312] ESMS m/z 371 (H), C₂₄H₂₂N₂O₂=370 g/mol, HPLC purity=95%.

[0313] 5.1.2.48 Synthesis of4-{4-ethyl-5-(4-hydroxyphenyl)-1-[4-(methylethyl)phenyl]pyrazol-3-yl}phenol

[0314] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 4-iso-propylphenyl hydrazine was used asthe reagent to form pyrazole.

[0315] ESMS m/z 399 (MH⁺), C₂₆H₂₆N₂O₂=398 g/mol, HPLC purity=95%.5.1.2.49 Synthesis of 4-[4-ethyl-1(3fluorophenyl)-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol This compound wassynthesized in the same manner described in Section 5.1.2.46. In step 2,3-fluorophenyl hydrazine was used as the reagent to form pyrazole.

[0316] ESMS m/z 375 (MH⁺), C₂₃H₁₉FN₂O₂=374 g/mol, HPLC purity=95%.

[0317] 5 5.1.2.50 Synthesis of4-[4-ethyl-1-(2-ethylpheny)-5-(4-hydroxyphenyl)pyrazol-3yl]phenol

[0318] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 2-ethylphenyl hydrazine was used as thereagent to form pyrazole.

[0319] ESMS m/z 385 (MH⁺), C₂₅H₂₄N₂O₂=384 g/mol, HPLC purity=95%.

[0320] 5.1.2.51 Synthesis of4-[4-ethyl-l-(4-fluorophenyl)-5-(4-hydroxyphenyl)pyrazol-3-yl)phenol

[0321] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 4-fluorophenyl hydrazine was used as thereagent to form pyrazole.

[0322] ESMS m/z 375 (MH⁺), C₂₃H₁₉FN₂O₂=374 g/mol, HPLC purity=95%.

[0323] 5.1.2.52 Synthesis of4-[1-(2,4-difluorophenyl)4-ethyl-5(4-hydroxyphenyl)pyrazol-3-yl]phenol

[0324] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 2,4-difluorophenyl hydrazine was used asthe reagent to form pyrazole.

[0325] ESMS m/z 393 (MH⁺), C₂₃H₁₈F₂N₂O₂=392 g/mol, HPLC purity=80%.

[0326] 5.1.2.53 Synthesis of4-[4-ethyl-5-(4-hydroxyphenyl)-1-[2-(trifluoromethyl)phenyl]pyrazol-3-yl}phenol

[0327] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 2-trifluoromethylphenyl hydrazine was usedas the reagent to form pyrazole.

[0328] ESMS m/z 425 (MH⁺), C₂₄H₁₉F₃N₂O₂=424 g/mol, HPLC purity=90%.

[0329] 5.1.2.54 Synthesis of4-[4-ethyl-1-(2-fluorophenyl)-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol

[0330] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 2-fluorophenyl hydrazine was used as thereagent to form pyrazole.

[0331] ESMS m/z 375 (MH⁺), C₂₃H₁₉FN₂O₂=374 g/mol, HPLC purity=85%.

[0332] 5.1.2.55 Synthesis of4-[4-ethyl-5-(4-hydroxypheny)-1-(2-methypheny)pyrazol-3-y]phenol

[0333] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 2-methylphenyl hydrazine was used as thereagent to form pyrazole.

[0334] ESMS m/z 371 (MH⁺), C₂₄H₂₂N₂O₂=370 g/mol, HPLC purity=85%.

[0335] 5.1.2.56 Synthesis of4-[1-(3,5-dichlorophenyl)-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol

[0336] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 3,5-dichlorophenyl hydrazine was used asthe reagent to form pyrazole.

[0337] ESMS m/z 426 (MH⁺), C₂₃H₁₈Cl₂N₂O₂=424 g/mol, HPLC purity=90%.

[0338] 5.1.2.57 Synthesis of4-1-(4chloro-2-methylphenyl)-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol

[0339] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 4-chloro-2-methylphenyl hydrazine was usedas the reagent to form pyrazole.

[0340] ESMS m/z 405 (MH⁺), C₂₄H₂₁ClN₂O₂=404 g/mol, HPLC purity=85%.

[0341] 5.1.2.58 Synthesis of4-[4-ethyl-5-(4-hydroxyphenyl)-1-(4-methylphenyl)pyrazol-3-yl]phenol

[0342] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 4-methylphenyl hydrazine was used as thereagent to form pyrazole.

[0343] ESMS m/z 371 (MH⁺), C₂₄H₂₂N₂O₂=370 g/mol, HPLC purity=80%.

[0344] 5.1.2.59 Synthesis of4-1-(2,3-dichlorophenyl)4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol

[0345] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 2,3-dichlorophenyl hydrazine was used asthe reagent to form pyrazole.

[0346] ESMS m/z 425 (MH⁺), C₂₃H₁₈Cl₂N₂O₂=424 g/mol, HPLC purity=85%.

[0347] 5.1.2.60 Synthesis of4-[1-(3,4-methylphenyl)-4-ethyl-5-(4-hydroxyphenyl)pyrazol-yl]phenol

[0348] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 3,4-dimethylphenyl hydrazine was used asthe reagent to form pyrazole.

[0349] ESMS m/z 385 (MH⁺), C₂H₂₄N₂O₂=384 g/mol, HPLC purity=95%.

[0350] 5.1.2.61 Synthesis of4-[4-ethyl-1-(5-fluoro-2-methyphenyl)-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol

[0351] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 5-fluoro-2-methylphenyl hydrazine was usedas the reagent to form pyrazole.

[0352] ESMS m/z 389 (MH⁺), C₂₄H₂₁FN₂O₂=388 g/mol, HPLC purity=95%.

[0353] 5.1.2.62 Synthesis of4-[1-(2chlorophenyl)4-ethyl-5(4-hydroxyphenyl)pyrazol-3-yl]phenol

[0354] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 2-chlorophenyl hydrazine was used as thereagent to form pyrazole.

[0355] ESMS m/z 391 (MH⁺), C₂₃H₁₉ClN₂O₂=390 g/mol, HPLC purity=95%.

[0356] 5.1.2.63 Synthesis of4-{1-[4-(tert-butyl)phenyl]4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol

[0357] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 4-t-butylphenyl hydrazine was used as thereagent to form pyrazole.

[0358] ESMS m/z 413 (MH⁺), C₂₇H₂₈N₂O₂=412 g/mol, HPLC purity=95%.

[0359] 5.1.2.64 Synthesis of4-[1-(3chiorophenyl)4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol

[0360] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 3-chlorophenyl hydrazine was used as thereagent to form pyrazole.

[0361] ESMS m/z 391 (MH⁺), C₂₃H₁₉ClN₂O₂=390 g/mol, HPLC purity=90%.

[0362] 5.1.2.65 Synthesis of4-[1-(2,4-dichlorophenyl)-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol

[0363] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 2,4-dichlorophenyl hydrazine was used asthe reagent to form pyrazole.

[0364] ESMS m/z 425 (MH⁺), C₂₃H₁₈Cl₂N₂O₂=424 g/mol, HPLC purity=85%.

[0365] 5.1.2.66 Synthesis of4-[1-(3,4-dichlorophenyl)4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol

[0366] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 3,4-dichlorophenyl hydrazine was used asthe reagent to form pyrazole.

[0367] ESMS m/z 425 (MH⁺), C₂₃H₁₈Cl₂N₂O₂=424 g/mol, HPLC purity=85%.

[0368] 5.1.2.67 Synthesis of4-[1-(4-chlorophenyl)-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol

[0369] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 4-chlorophenyl hydrazine was used as thereagent to form pyrazole.

[0370] ESMS m/z 391 (MH⁺), C₂₃H₁₉CIN₂0₂ =390 g/mol, HPLC purity =80%.

[0371] 5.1.2.68 Synthesis of4-11-(2,6-dichlorophenyl)4-ethyl-5(4-hydroxyphenyI)pyrazol-3-yl]phenolThis compound was synthesized in the same manner described in Section5.1.2.46. In step 2, 2,5-dichlorophenyl hydrazine was used as thereagent to form pyrazole.

[0372] ESMS m/z 425 (MH⁺), Chd 23H18Cl₂N₂O₂=424 g/mol, HPLC purity=95%.

[0373] 5.1.2.69 Synthesis of4-[1-(2,3-dimethylphenyi)Aethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol

[0374] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 2,3-dimethylphenyl hydrazine was used asthe reagent to form pyrazole.

[0375] ESMS m/z 385 (MH⁺), C₂₅H₂₄N₂O₂=384 g/mol, HPLC purity=95%.

[0376] 5.1.2.70 Synthesis of4-[1-(3-chloro-4-fluorophenyl)-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol

[0377] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 3-chloro4-trifluorophenyl hydrazine wasused as the reagent to form pyrazole.

[0378] ESMS m/z 409 (MH⁺), C₂₃H₁₈CIFN₂O₂=408 g/mol, HPLC purity=99%.

[0379] 5.1.2.71 Synthesis of4-{4-ethyl-5-(4-hydroxyphenyl)-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl}phenol

[0380] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 4-trifluoromethoxyphenyl hydrazine was usedas the reagent to form pyrazole.

[0381] ESMS m/z 441 (MH⁺), C₂₄H₁₉F₃N₂O₃=440 g/mol, HPLC purity=95%.

[0382] 5.1.2.72 Synthesis of4-{4-ethyl-5(4-hydroxyphenyl)-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl}phenol

[0383] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 4-trifluoromethylphenyl hydrazine was usedas the reagent to form pyrazole.

[0384] ESMS m/z 425 (MH⁺), C₂₄H₁₉F₃N₂O₂=424 g/mol, HPLC purity=60%.

[0385] 5.1.2.73 Synthesis of4-[4-ethyl-5-(4-hydroxyphenyl)-1-(4-iodophenyl)pyrazol-3-yl]phenol

[0386] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 4-iodophenyl hydrazine was used as thereagent to form pyrazole.

[0387] ESMS m/z 482 (MH⁺), C₂₃H₁₉IN₂O₂=481 g/mol, HPLC purity=60%.

[0388] 5.1.2.74 Synthesis of4-(1-[2-chloro-5(trifluoromethyl)phenyl]-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl}phenol

[0389] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 2-chloro-5-trifluoromethylphenyl hydrazinewas used as the reagent to form pyrazole.

[0390] ESMS m/z 459 (MH⁺), C₂₄H₁₈ClF₃N₂O₂=458 g/mol, HPLC purity=95%.

[0391] 5.1.2.75 Synthesis of4-[1-(3,5-dichloro(4-pyridyl))-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol

[0392] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 3,5-dichloro-4-pyridylhydrazine was used asthe reagent to form pyrazole.

[0393] ESMS m/z 427 (MH⁺), C₂₅H₁₇Cl₂N₃O₂=426 g/mol, UPLC purity=85%.

[0394] 5.1.2.76 Synthesis of4-{4-ethyl-5-(4-hydroxyphenyl)-1-[6-methyl-(trifluoromethyl)(2-pyridyl)]pyrazol-3-yl]phenol

[0395] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2,3-methyl-5-trifluoromethyl-2-pyridylhydrazine was used as the reagent toform pyrazole.

[0396] ESMS m/z 440 (MH⁺), C₂₄H₂₀F₃N₃O₂=439 g/mol, HPLC purity=85%.

[0397] 5.1.2.77 Synthesis of4-[4-ethyl-5-(4-hydroxyphenyl)-1quinoxalin-2-ylpyrazol-3-yl]phenol

[0398] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, quinoxaline-2-ylhydrazine was used as thereagent to form pyrazole.

[0399] ESMS m/z 409 (MH⁺), C₂₅H₂₀N₄O₂=408 g/mol, RPLC purity=70%.

[0400] 5.1.2.78 Synthesis of4-{1-[3,5-bis(trifluoromethyl)phenyl]-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl)phenol

[0401] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 3,5-ditrifluoromethylphenyl hydrazine wasused as the reagent to form pyrazole.

[0402] ESMS m/z 493 (MH⁺), C₂₅H₁₈F₆N₂O₂=492 g/mol, HPLC purity=80%.

[0403] 5.1.2.79 Synthesis of4-[3,5bis(4-hydroxyphenyl)-4-ethylpyrazolyl]benzenesulfonamide

[0404] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 4-(methylsulfonyl)phenylhydrazine was usedas the reagent to form pyrazole.

[0405] ESMS m/z 436 (MH⁺), C₂₃H₂₁N₃O₄S=435 g/mol, HPLC purity=70%.

[0406] 5.1.2.80 Synthesis of4-[1-(1,3-dimethyl-5-nitropyrazol-4-y)4-ethyl-3-(4-hydroxypheny)pyrazol-5-yl]phenol

[0407] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 1,3-dimethyl-5-nitropyrazole-4-ylhydrazinewas used as the reagent to form pyrazole.

[0408] ESMS m/z 420 (MH⁺), C₂₂H₂₁N₅O₄=419 g/mol, HPLC purity=70%.

[0409] 5.1.2.81 Synthesis of4-{1-[5chloro-3-(tfifluoromethyl)(2-pyridyl)]4ethyl-5-(4-hydroxyphenyl)pyrazol-3-ylophenol

[0410] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2,5-chloro-3-trifluoromethyl-2-pyridylhydrazine was used as the reagent toform pyrazole.

[0411] ESMS m/z 460 (MH⁺), C₂₃H₁₇ClF₃N₃O₂=459 g/mol, HPLC purity=85%.

[0412] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2,3-chloro-5-trifluoromethyl-2-pyridythydrazine was used as the reagent toform pyrazole.

[0413] ESMS m/z 460 (MH⁺), C₂₃H₁₇ClF₃N₃O₂=459 g/mol, HPLC purity=85%.

[0414] 5.1.2.83 Synthesis of 4-[4-ethyl-5-(4-hydroxyphenyl)-1 -(1,3,4-trimethylpyrazolo[4,5-e]pyridin-6-yl)pyrazol-3-yl]phenol

[0415] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2,1,3,4-trimethylpyrazolo[5,4-b]pyridine-6-ylhydrazine was used as thereagent to form pyrazole.

[0416] ESMS m/z 440 (MH⁺), C₂₆H₂₅N₅O₂=439 g/mol, HPLC purity=80%.

[0417] 5.1.2.84 Synthesis of4-[1-(6-chloro-2-fluorophenyl)-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol

[0418] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 2-chloro-6-fluorophenyl hydrazine was usedas the reagent to form pyrazole.

[0419] ESMS m/z 409(MH⁺), C₂₃H₁₈ClFN₂O₂=408 g/mol, HPLC purity=85%.

[0420] 5.1.2.85 Synthesis of4-[4-ethyl-5-(4-hydroxyphenyl)-1-(2-pyridyl)pyrazol-3-yl]phenol

[0421] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 2-pyridylhydrazine was used as the reagentto form pyrazole.

[0422] ESMS m/z 358 (MH⁺), C₂₂H₁₉N₃O₂=357 g/mol, HPLC purity=90%

[0423]5.1.2.86 Synthesis of4-[4-ethyl-1-(3-hexadecylthiophenyl)-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol

[0424] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 3-hexadecylthiophenylhydrazine was used asthe reagent to form pyrazole.

[0425] ESMS m/z 613 (MH⁺), C₃₉H₅₂N₂O₂S=612 g/mol, HPLC purity=50%.

[0426]5.1.2.87 Synthesis of4-[3,5-bis(4-hydroxyphenyl)-1-(3-hexadecylthiophenyl)pyrazol-4-yl]phenol

[0427] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 3-hexadecylthiophenylhydrazine was used asthe reagent to form pyrazole.

[0428] ESMS m/z 677 (MH⁺), C₄₃H₅₂N₂O₃S=676 g/mol, HPLC purity=50%.

[0429]5.1.2.88 Synthesis of4-{4-ethyl-5-(4-hydroxyphenyl)-1-[(4-hydroxyphenyl)methyl]pyrazol-3-yl}phenol

[0430] This compound was synthesized based upon Scheme 4.

[0431] Step 1: To a solution of 4′-methoxybutyryl phenone (1.0 equiv.)in THF at −78° C. was added dropwise 1.5 equiv. of [(CH₃)₂Si]₂NLi. Thesolution was stirred for 1 h at −78° C., followed by addition of 1.2equiv. of p-anisoyl chloride. The reaction mixture was stirred for 10min at −78° C. and then for 22 h at rt, acidified with 10% citric acid,and extracted with EtOAc. The combined organic layers were washed withwater and dried over Na₂SO₄. Removal of solvent in vacuo provided acrude solid which was purified by flash chromatography (CH₂Cl₂) to give1,3-bis(4-methoxyphenyl) -2-ethylpropane-1,3-dione.

[0432] Step 2: A mixture of the 1,3-diketone obtained in step 1 (1.0equiv.), hydrazine (3.0 equiv.), conc. HCl aq. (catalytic amount) andethanol was heated to reflux overnight. Cooled to rt and removed solventin vacuo. Water and ethyl acetate were added. The organic layer wasseparated, washed with dil. HCl, brine, dried, filtered and the solventwas concentrated in vacuo to give the product4-methoxy-1-[5-(4-methoxyphenyl)-4-benzylpyrazol-3-yl]benzene.

[0433] Step 3: Alkylation. Reaction was carried out in oven-driedglassware under nitrogen. Diketone (obtained from the above step) in DMFwas added to a chilled suspension of NaH (1.1 equiv.) in DMF. Themixture was allowed to stir for 5 min after which the 4′-methoxybenzylbromide was added (2.0 equiv.). The reaction was then allowed to stirover night at RT. Ethyl acetate was then added and the reaction waswashed with 10% citric acid, 10% NaHCO₃ and brine. After drying overNa₂SO₄ the solvent was removed. Products required purification which wasachieved with flash chromatography (10% EtOAc/petrol).

[0434] Step 4: Demethylation was performed as described in Scheme 1 toafford the final product.

[0435]¹H NMR (d₆-DMSO): δ 0.83 (3H, t, J=7.3 Hz), 2.38 (2H, q, J=7.3Hz), 4.94 (2H, s), 6.58 (2H, d, J=8.4 Hz), 6.74 (2H, d, J=8.4 Hz), 6.76(2H, d, J=8.4 Hz), 6.81 (2H, d, J=8.8 Hz), 7.05 (2H, d, J=8.4 Hz), 7.39(2H, d, J=8.8 Hz); ESMS m/z 387 (MH+), C₂₄H₂₂N₂O₃=386 g/mol; HPLCpurity=96%.

[0436]5.1.2.89 Synthesis of4-(4-ethyl-5-(4-hydroxypheny)-1-{[4-(2-piperidylethoxy)phenyl]methyl}pyrazol-3-yl)phenol

[0437] This compound was synthesized in the same manner as described inSection 5.1.2.88. In step 3,4-(chloromethyl)-1-(2-piperidylethoxy)benzene was used for alkylation.

[0438]¹H NMR (acetone): δ 0.93 (3H, t, J=7.4 Hz), 1.42-1.57 (1H, m),1.72-2.05 (5H, m), 2.49 (2H, q, J=7.4 Hz), 3.07-3.18 (2H, m), 3.54-3.58(2H, m), 3.62-3.71 (2H, m), 3.83 (3H, m), 4.44 (2H, t, J=5.1 Hz), 5.08(2H, s), 6.82 (2H, d, J=7.8 Hz), 6.87 (2H, d, J=8.8 Hz), 6.92 (2H, d,J=8.6 Hz), 6.98 (2H, d, J=7.5 Hz), 7.10 (2H, d, J=8.2 Hz), 7.55 (2H, d,J=8.0 Hz); ESMS m/z 498 (MH+), C₃₁H₃₅N₃O₃=497 g/mol; HPLC purity=97.9%.

[0439] 5.1.2.90 Synthesis of4-{1-[(3chlorophenyl)methyl]-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl}phenol

[0440] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, 3′-chlorobenzyl chloride was used foralkylation.

[0441]¹H NMR (CDCl₃): δ 0.75 (3H, t, J=7.5 Hz), 2.30 (2H, q, J=7.5 Hz),4.95 (2H, s), 6.67-6.73 (5H, m), 6.77-6.80 (1H, m), 6.87 (2H, dd, J=5.5,1.6 Hz), 7.30 (2H, d, J=8.8 Hz); ESMS m/z 405 (MH+), C₂₄H₂₁ClN₂O₂=404g/mol; HPLC purity=92.7%.

[0442] 5.1.2.91 Synthesis of4-{4-ethyl-1-[(4-fluorophenyl)methyl]-5-(4-hydroxyphenyl)pyrazol-3-yl}phenol

[0443] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, 4′-fluorobenzyl chloride was used foralkylation.

[0444]¹H NMR (CDCl₃): δ 0.79 (3H, t, J=7.5 Hz), 2.33 (2H, q, J=7.5 Hz),4.99 (2H, s), 6.71-6.84 (8H, m), 6.90 (2H, d, J=8.4 Hz), 7.34 (2H, d,J=8.4 Hz); ESMS m/z 389 (MH+), C₂₄H₂₁FN₂O₂=388 g/mol; HPLC purity=90.8%.

[0445] 5.1.2.92 Synthesis of4-{4-ethyl-5-(4-hydroxyphenyl)-1-[(3-methylphenyl)methyl]pyrazol-3-yl}phenol

[0446] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, 3′-methylbenzyl chloride was used foralkylation.

[0447]¹H NMR (CDCl₃): δ 0.85 (3H, t, J=7.5 Hz), 2.18 (3H, s), 2.40 (2H,q, J=7.5 Hz), 5.04 (2H, s), 6.68 (1H, d, J=7.4 Hz), 6.71 (1H, s), 6.78(2H, d, 8.0 Hz), 6.80 (2H, d, 8.0 Hz), 6.93 (1H, d, J=7.4 Hz), 6.97 (2H,d, J=8.8 Hz), 7.03 (1H, t, J=7.4 Hz), 7.39 (2H, d, J=8.8 Hz); ESMS m/z385 (MH+), C₂₅H₂₄N₂O₂=384 g/mol; HPLC purity=87.6%.

[0448] 5.1.2.93 Synthesis of4-{4-ethyl-5-(4-hydroxyphenyl)-1-[(4-nitrophenyl)methyl]pyrazol-3-yl}phenol

[0449] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, 4′-nitrobenzyl chloride was used foralkylation.

[0450]¹H NMR (CDCl₃): δ 0.60 (3H, t, J=7.5 Hz), 2.17 (2H, q, J=7.5 Hz),4.93 (2H, s), 6.51 (2H, d, J=8.8 Hz), 6.54 (2H, d, J=8.8 Hz), 6.69 (2H,d, J=8.8 Hz), 6.80 (2H, d, J=8.8 Hz), 7.12 (2H, d, J=8.8 Hz), 7.77 (2H,d, J=8.8 Hz); ESMS m/z 416 (MH+), C₂₄H₂₁N₃O₄=415 g/mol; HPLCpurity=83.5%.

[0451] 5.1.2.94 Synthesis of4-{4-ethyl-5-(4-hydroxyphenyl)-1-[(3-phenoxyphenyl)methyl]pyrazol-3-yl}phenol

[0452] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, 3′-phenoxybenzyl chloride was used foralkylation.

[0453]¹H NMR (CDCl₃): δ 0.90 (3H, t, J=7.5 Hz), 2.38 (2H, q, J=7.5 Hz),5.04 (2H, s), 6.43 (1H, m), 6.65 (1H, d, J=7.1 Hz), 6.73-6.87 (7H, m),6.93 (2H, dd, J=8.6, 2.4 Hz), 7.01 (1H, t, J=7.2 Hz), 7.13 (1H, t, J=7.9Hz, 7.19-7.25 (2H, m), 7.34 (2H, d, J=8.6 Hz); ESMS m/z 463 (MH+),C₃₀H₂₆N₂O₃=462 g/mol; HPLC purity=78.5%.

[0454] 5.1.2.95 Synthesis of2-[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]-1-(4-methylphenyl)ethan-1-one

[0455] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, 2-chloro-1-(4-methylphenyl)ethan-1-one wasused for alkylation.

[0456]¹H NMR (CDCl₃): δ 0.89 (3H, t, J=7.5 Hz), 2.32 (3H, s), 2.44 (2H,q, J=7.5 Hz), 5.30 (2H, s), 6.77 (2H, d, J=9.2 Hz), 6.80 (2H, d, J=9.2Hz), 7.06 (2H, d, J=8.1 Hz), 7.18 (2H, d, J=8.8 Hz), 7.41 (2H, d, J=8.8Hz), 7.69 (2H, d, J=8.1 Hz); ESMS m/z 413 (MH+), C₂₆H₂₄N₂O₃=412 g/mol;HPLC purity=90.8%.

[0457] 5.1.2.96 Synthesis of2-[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]-1-(4-fluorophenyl)ethan-1-one

[0458] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, 2-chloro-1-(4-fluorophenyl)ethan-1-one wasused for alkylation.

[0459]¹H NMR (CDCl₃): δ 0.86 (3H, t, J=7.5 Hz), 2.41 (2H, q, J=7.5 Hz),5.29 (2H, s), 6.74 (2H, d, J=8.8 Hz), 6.76 (2H, d, J=8.8 Hz), 7.02 (2H,d, J=8.6 Hz), 7.05 (2H, d, J=8.8 Hz), 7.36 (2H, d, J=8.8 Hz), 7.80 (2H,dd, J=8.8, 5.1 Hz); ESMS m/z 417 (MH+), C₂₅H₂₁FN₂O₃=416 g/mol; HPLCpurity=83.1%.

[0460] 5.1.2.97 Synthesis of1-(3,4dichlorophenyl)-2-[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]ethan-1-one

[0461] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, 2-chloro-1-(3,4-dichlorophenyl)ethan-1-onewas used for alkylation.

[0462]¹H NMR (CDCl₃): δ 0.88 (1.5H, t, J=7.5 Hz), 0.96 (1.5H, t, J=7.5Hz), 2.43 (1H, q, J=7.5 Hz), 2.52 (1H, q, J=7.5 Hz), 5.30 (1H, s),6.77-6.86 (4H, m), 7.05 (1H, d, J=8.8 Hz), 7.32 (2H, t, J=8.6 Hz),7.46-7.53 (1.5H, m), 7.64 (0.5H, dd, J=8.4, 2.4 Hz), 7.78-7.88 (0.5H,m), 7.79-8.10 (0.5H, m); ESMS m/z 467 (MH+), C₂₅H₂₀Cl₂N₂O₃=466 g/mol;HPLC purity=82.7%.

[0463] 5.1.2.98 Synthesis of2-[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]-1-(2-hydroxyphenyl)ethan-1-one

[0464] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, 2-chloro-1-(2-methoxyphenyl)ethan-1-one wasused for alkylation.

[0465]¹H NMR (CDCl₃): δ 0.89 (3H, t, J=7.5 Hz), 2.45 (2H, q, J=7.5 Hz),3.67 (2H, s), 5.38 (1H, s), 6.76-6.90 (6H, m), 7.08 (2H, d, J=8.8 Hz),7.39-7.44 (3H, m), 7.58 (1H, dd, J=7.4, 2.5 Hz), 7.29-7.50 (3H, m), 7.69(2H, d, J=8.8 Hz); ESMS m/z 415 (MH+), C₂₅H₂₂N₂O₄=414 g/mol; HPLCpurity=90.7%.

[0466] 5.1.2.99 Synthesis of4-[4-ethyl-5-(4-hydroxyphenyl)-1-benzylpyrazol-3-yl]phenol

[0467] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, benzylbromide was used for alkylation.

[0468]¹H NMR (CDCl₃): δ 0.86 (3H, t, J=7.5 Hz), 2.41 (2H, q, J=7.5 Hz),5.10 (2H, s), 6.77 (2H, d, J=8.8 Hz), 6.80 (1H, d, J=8.8 Hz), 6.90 (2H,d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.10-7.19 (3H, m), 7.40 (2H, d,J=8.8 Hz); ESMS m/z 371 (MH+), C₂₄H₂₂N₂O₂=370 g/mol; HPLC purity=90.0%.

[0469] 5.1.2.100 Synthesis of2-[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]-1-(4-bromophenyl)ethan-1-one

[0470] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, 2-chloro-1-(4bromophenyl)ethan-1-one wasused for alkylation.

[0471] ESMS m/z 477/479 (MH+), C₂₅H₂₁BrN₂O₃=476/478 g/mol; HPLCpurity=80.8%.

[0472] 5.1.2.101 Synthesis of4-{[4-(tert-butyl)phenyl]methyl}-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl)phenol

[0473] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, 4′-t-butylbenzyl chloride was used foralkylation.

[0474]¹H NMR (CDCl₃): δ 0.85 (3H, t, J=7.5 Hz), 1.19 (9H, s), 2.48 (2H,q, J=7.5 Hz), 5.05 (2H, s), 6.77 (2H, d, J=8.8 Hz), 6.79 (2H, d, J=8.9Hz), 6.84 (2H, d, J=8.9 Hz), 6.99 (2H, d, J=8.9 Hz), 7.18 (2H, d, J=8.9Hz), 7.38 (2H, d, J=8.9 Hz); ESMS m/z 427 (MH+), C₂₈H₃₀N₂O₂=426 g/mol;HPLC purity=86.1%.

[0475] 5.1.2.102 Synthesis of4-{2-[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]acetyl}benzenecarbonitrile

[0476] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, 2-chloro-1-(4-cyanophenyl)ethan-1-one wasused for alkylation.

[0477]¹H NMR (CDCl₃): δ 0.88 (3H, t, J=7.5 Hz), 2.44 (2H, q, J=7.5 Hz),5.28 (2H, s), 6.78 (2H, d, J=8.8 Hz), 6.82 (2H, d, J=9.1 Hz), 7.04 (2H,d, J=9.6 Hz), 7.40 (2H, d, J=8.4 Hz), 7.69 (2H, d, J=8.8 Hz), 7.86 (2H,d, J=8.8 Hz); ESMS m/z 424 (MH+), C₂₆H₂₁N₃O₃=423 g/mol; HPLCpurity=81.8%.

[0478] 5.1.2.103 Synthesis of2-[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]-1-(4-phenylphenyl)ethan-1-one

[0479] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, 2-chloro-1-(4-phenylphenyl)ethan-1-one wasused for alkylation.

[0480]¹H NMR (CDCl₃): δ 0.89 (3H, t, J=7.5 Hz), 2.45 (2H, q, J=7.5 Hz),5.38 (2H, s), 6.77 (2H, d, J=8.8 Hz), 6.81 (2H, d, J=9.2 Hz), 7.08 (2H,d, J=8.8 Hz), 7.29-7.45 (5H, m), 7.54 (2H, d, J=8.8 Hz), 7.62 (2H, d,J=8.8 Hz), 7.86 (2H, d, J=8.4 Hz); ESMS m/z 475 (MH+), C₃₁H₂₆N₂O₃=474g/mol; HPLC purity=90.9%.

[0481] 5.1.2.104 Synthesis of2-[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]-1-(3-hydroxyphenyl)ethan-1-one

[0482] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, 2-chloro-1-(3-methoxyphenyl)ethan-1-one wasused for alkylation.

[0483]¹H NMR (CDCI₃): δ 0.79 (3H, t, J=7.5 Hz), 2.33 (2H, q, J=7.5 Hz),5.19 (2H, s), 6.66 (2H, d, J=8.8 Hz), 6.70 (2H, d, J=8.8 Hz), 6.87 (1H,ddd, J=7.9, 2.6, 1.1 Hz), 6.96 (2H, d, J=8.6, 2.5 Hz), 7.07-7.16 (3H,m), 7.31 (2H, d, J=8.8 Hz); ESMS m/z 415 (MH+), C₂₅H₂₂N₂O₄=414 g/mol;HPLC purity=84.9%.

[0484] 5.1.2.105 Synthesis of4-[1-(2,4-dimethylphenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol

[0485] This compound was synthesized based upon Scheme 1.

[0486] Step 1: To a solution of 1-(4-methoxyphenyl)-2-phenylethan-1-one(1.0 equiv.) in THF at −78° C. was added dropwise 1.5 equiv. of[(CH₃)₂Si]₂NLi. The solution was stirred for 1 h at −78° C., followed byaddition of 1.2 equiv. of p-anisoyl chloride. The reaction mixture wasstirred for 10 min at −78° C. and then for 22 h at rt, acidified with10% citric acid, and extracted with EtOAc. The combined organic layerswere washed with water and dried over Na₂SO₄. Removal of solvent invacuo provided a crude solid which was purified by flash chromatography(CH₂Cl₂) to give 1,3-bis(4-methoxyphenyl)-2-phenylpropane-1,3-dione.

[0487] Step 2: A mixture of the 1,3-diketone obtained in step 1 (1.0equiv.), 2,4-dimethylphenyl hydrazine (1.5 equiv.), conc. HCl aq.(catalytic amount) and ethanol was heated to reflux overnight. Cooled tort and removed solvent in vacuo. Water and ethyl acetate were added. Theorganic layer was separated, washed with dil. HCl, brine, dried,filtered and the solvent was concentrated in vacuo to give the product.

[0488] Step 3: Demethylation was performed as described in Scheme 1 toafford the final product.

[0489] ESMS m/z 433 (MH⁺), C₂₉H₂₄N₂O₂=432 g/mol, HPLC purity=90%.5.1.2.106 Synthesis of4-[5-(4-hydroxyphenyl)-1-(3-methylphenyl)-4-phenylpyrazol-3-yl]phenol

[0490] This compound was synthesized in the same manner as described inSection 5.1.2.105. In step 2, 3-methylphenyl hydrazine was used to formthe pyrazole heterocycle.

[0491] ESMS m/z 419 (MH⁺), C₂₈H₂₂N₂O₂=418 g/mol, HPLC purity=90%.

[0492] 5.1.2.107 Synthesis of4-{5-(4-hydroxyphenyl)-1-[4-(methylethyl)phenyl]-4-phenylpyrazol-3-yl}phenol

[0493] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 4-iso-propylphenyl hydrazine was used toform the pyrazole heterocycle.

[0494] ESMS m/z 447 (MH⁺), C₃₀H₂₆N₂O₂=446 g/mol, HPLC purity=90%.

[0495] 5.1.2.108 Synthesis of4-[1-(3-fluorophenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol

[0496] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 3-fluorophenyl hydrazine was used to formthe pyrazole heterocycle.

[0497] ESMS m/z 423 (MH⁺), C₂₇H₁₉FN₂O₂=422 g/mol, HPLC purity=90%.

[0498] 5.1.2.109 Synthesis of4-[1-(2-ethylphenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol

[0499] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 2-ethylphenyl hydrazine was used to formthe pyrazole heterocycle.

[0500] ESMS m/z 433 (MH⁺), C₂₉H₂₄N₂O₂=432 g/mol, HPLC purity=90%.

[0501] 5.1.2.110 Synthesis of4-[1-(4-fluorophenyl)-3-(4-hydroxyphenyl)-4-phenylpyrazol-5-yl]phenol

[0502] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 4-fluorophenyl hydrazine was used to formthe pyrazole heterocycle.

[0503] ESMS m/z 423 (MH⁺), C₂₇H₁₉FN₂O₂=422 g/mol, HPLC purity=90%.

[0504] 5.1.2.111 Synthesis of4-[1-(2,4-difluorophenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol

[0505] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 2,4-difluorophenyl hydrazine was used toform the pyrazole heterocycle.

[0506] ESMS m/z 441 (MH⁺), C₂₇H₁₈F₂N₂O₂=440 g/mol, HPLC purity=90%.

[0507] 5.1.2.112 Synthesis of4-{5-(4-hydroxyphenyl)-4-phenyl-1-[2-(trifluoromethyl)phenyl]pyrazol-3-yl}phenol

[0508] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 2-trifluoromethylphenyl hydrazine was usedto form the pyrazole heterocycle.

[0509] ESMS m/z 473 (MH⁺), C₂₈H₁₉F₃N₂O₂=472 g/mol, HPLC purity=90%.

[0510] 5.1.2.113 Synthesis of4-[1-(2-fluorophenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol

[0511] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 2-fluorophenyl hydrazine was used to formthe pyrazole heterocycle.

[0512] ESMS m/hz 423 (MH⁺), C₂₇H₁₉FN₂O₂=422 g/mol, HPLC purity=90%.5.1.2.114 Synthesis of4-[5-(4-hydroxyphenyl)-1-(2-methylphenyl)-4-phenylpyrazol-3-yl]phenol

[0513] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 2-methylphenyl hydrazine was used to formthe pyrazole heterocycle.

[0514] ESMS m/z 419 (MH⁺), C₂₈H₂₂N₂O₂=418 g/mol, HPLC purity=90%.

[0515] 5.1.2.115 Synthesis of4-[1-(3,5-dichlorophenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol

[0516] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 3,5-dichlorophenyl hydrazine was used toform the pyrazole heterocycle.

[0517] 5 ESMS m/z 473 (MH⁺), C₂₇H₁₈Cl₂N₂O₂=472 g/mol, HPLC purity=90%.

[0518] 5.1.2.116 Synthesis of4-[1-(4-chloro-2-methylphenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol

[0519] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 4-chloro-2-methylphenyl hydrazine was usedto form the pyrazole heterocycle.

[0520] ESMS m/z 453 (MH⁺), C₂₈H₂₁ClN₂O₂=452 g/mol, HPLC purity=90%.

[0521] 5.1.2.117 Synthesis of4-[3-(4-hydroxyphenyl)-1-(4-methylphenyl)-4-phenylpyrazol-5-yl]phenol

[0522] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 4-methylphenyl hydrazine was used to formthe pyrazole heterocycle.

[0523] ESMS m/z 419 (MH⁺), C₂₈H₂₂N₂O₂=418 g/mol, HPLC purity=90%.

[0524] 5.1.2.118 Synthesis of4-[1-(2,3-dichlorophenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol

[0525] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 2,3-dichlorophenyl hydrazine was used toform the pyrazole heterocycle.

[0526] ESMS m/z 473 (MH⁺), C₂₇H₁₈Cl₂N₂O₂=472 g/mol, HPLC purity=90%.

[0527] 5.1.2.119 Synthesis of4-[1-(3,4-dimethylphenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol

[0528] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 3,4-dimethylphenyl hydrazine was used toform the pyrazole heterocycle.

[0529] ESMS m/z 433 (MH⁺), C₂₉H₂₄N₂O₂=432 g/mol, HPLC purity=90%.

[0530] 5.1.2.120 Synthesis of4-[1-(5-fluoro-2-methylphenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol

[0531] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 5-fluoro2-methylphenyl hydrazine was usedto form the pyrazole heterocycle.

[0532] ESMS m/z 437 (MH⁺), C₂₈H₂₁FN₂O₂=436 g/mol, HPLC purity=90%.

[0533] 5.1.2.121 Synthesis of4-[1-(2-chlorophenyl)-5-(4-hydroxyphenyl)-4-phenypyrazol-3-yl]phenol

[0534] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 2-chlorophenyl hydrazine was used to formthe pyrazole heterocycle.

[0535] ESMS m/z 439 (MH⁺), C₂₇H₁₉ClN₂O₂=438 g/mol, HPLC purity=90%.5.1.2.122 Synthesis of4-[1-(3-chlorophenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol

[0536] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 3-chloro phenyl hydrazine was used to formthe pyrazole heterocycle.

[0537] ESMS m/z 439 (MH⁺), C₂₇H₁₉ClN₂O₂=438 g/mol, HPLC purity=90%.

[0538] 5.1.2.123 Synthesis of4-[1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol

[0539] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 2,4-dichlorophenyl hydrazine was used toform the pyrazole heterocycle.

[0540] ESMS m/z 473 (MH⁺), C₂₇H₁₈Cl₂N₂O₂=472 g/mol, HPLC purity=90%.

[0541] 5.1.2.124 Synthesis of4-[1-(3,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol

[0542] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 3,4-dichlorophenyl hydrazine was used toform the pyrazole heterocycle.

[0543] ESMS m/z 473 (MH⁺), C₂₇H₁₈Cl₂N₂O₂=472 g/mol, HPLC purity=90%.

[0544] 5.1.2.125 Synthesis of4-[1-(4-chlorophenyl)-3-(4-hydroxyphenyl)-4-phenylpyrazol-5-yl]phenol

[0545] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 4-chlorophenyl hydrazine was used to formthe pyrazole heterocycle.

[0546] ESMS m/z 439 (MH⁺), C₂₇H₁₉ClN₂O₂=438 g/mol, HPLC purity=90%.

[0547] 5.1.2.126 Synthesis of4-[1-(2,6-dichlorophenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol

[0548] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 2,5-dichlorophenyl hydrazine was used toform the pyrazole heterocycle.

[0549] ESMS m/z 473 (MH⁺), C₂₇H₁₈Cl₂N₂O₂=472 g/mol, HPLC purity=90%.

[0550] 5.1.2.127 Synthesis of4-[1-(2,3-dimethylphenyl)-5(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenof

[0551] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 2,3-dimethylphenyl hydrazine was used toform the pyrazole heterocycle.

[0552] ESMS m/z 433 (MH⁺), C₂₉H₂₄N₂O₂=432 g/mol, HPLC purity=90%.

[0553] 5.1.2.128 Synthesis of4-[1-(3-chloro-4-fluorophenyl)-5-(4-hydroxyphenyl)-4-phenyipyrazol-3-yl]phenol

[0554] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 3-chloro-4- fluorophenyl hydrazine wasused to form the pyrazole heterocycle.

[0555] ESMS m/z 457 (MH^(+), C) ₂₇H₁₈ClFN₂O₂=456 g/mol, HPLC purity=90%.

[0556] 5.1.2.129 Synthesis of4-{5-(4-hydroxypheny)-4-phenyl-1-[4-(trifluoromethoxy)phenyljpyrazol-3-yl}phenol

[0557] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 4-trifluoromethoxyphenyl hydrazine wasused to form the pyrazole heterocycle.

[0558] ESMS m/z 489 (MH⁺), C₂₈H₁₉F₃N₂O₃=488 g/mol, HPLC purity=90%.

[0559] 5.1.2.130 Synthesis of4-{5-(4-hydroxyphenyl)-4-phenyl-1-[4-(trifluoromethyi)phenyl]pyrazol-3-yl}phenol

[0560] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 4-trifluoromethylphenyl hydrazine was usedto form the pyrazole heterocycle.

[0561] ESMS m/z 473 (MH⁺), C₂₈H₁₉F₃N₂O₂=472 g/mol, HPLC purity=90%.

[0562] 5.1.2.131 Synthesis of4-[3-(4-hydroxyphenyl)-1-(4-iodophenyl)-4-phenylpyrazol-5-yl]phenol

[0563] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 4-iodophenyl hydrazine was used to formthe pyrazole heterocycle.

[0564] ESMS m/z 531 (MH⁺), C₂₇H₁₉IN₂O₂=530 g/mol, HPLC purity=90%.

[0565] 5.1.2.132 Synthesis of4-{1-[2-chloro-5-(trifluoromethy)phenyl]-5-(4-hydroxypheny)4-phenylpyrazol-3-yl}phenol

[0566] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 2-chloro5-trifluoromethylphenyl hydrazinewas used to form the pyrazole heterocycle.

[0567]¹H NMR (DMSO-d₆):δ6.56 (2H, d, J=8.61 Hz), 6.66 (2H, d, J=8.61Hz), 6.91 (2H, d, J=8.61 Hz), 7.12 (2H, d, J=8.06 Hz), 7.19 (2H, d,J=8.6 Hz), 7.22-7.29 (3H, m), 7.76 (2H, m), 8.08 (1H, s), 9.49 (1H, s),9.61 (1H, s); ESMS m/z 507 (MH⁺), C₂₈H₁₈ClF₃N₂O₂=496 g/mol; HPLCpurity=98.1%.

[0568] 5.1.2.133 Synthesis of 4-[1-(3,5-dichloro(4-pyridyl))-5-(4-hydroxyphenyl)-4-phenylpyrazo1-3-yl]phenol

[0569] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 3,5-dichloro-4- pyridyl hydrazine was usedto form the pyrazole heterocycle.

[0570] ESMS m/z 474 (MH⁺), C₂₆H₁₇Cl₂N₃O₂=473 g/mol, HPLC purity=90%.

[0571] 5.1.2.134 Synthesis of4-{-5-(4-hydroxypheny)-1-[6-methy-4-(trifluoromethyl)(2-pyddyl)]-4-phenypyrazol-3-yl}phenol

[0572] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 6-methyl-4-trifluoromethyl-2-pyridylhydrazine was used to form the pyrazole heterocycle.

[0573] ESMS m/z 488 (MH⁺), C₂₈H₂₀F₃N₃O₂=487 g/mol, HPLC purity=90%.

[0574] 5.1.2.135 Synthesis of4-[5-(4-hydroxyphenyl)-4-phenyl-1-quinoxalin-2-ylpyrazol-3-yl]phenol

[0575] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, quinoxaline-2-ylhydrazine was used to formthe pyrazole heterocycle.

[0576] ESMS m/z 457 (MH⁺), C₂₉H₂₀N₄O₂=456 g/mol, HPLC purity=90%.

[0577] 5.1.2.136 Synthesis of4-{1-[3,5-bis(trifluoromethyl)phenyl]-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl}phenol

[0578] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 3,5-di-trifluoromethylphenyl hydrazine wasused to form the pyrazole heterocycle.

[0579] ESMS m/z 541 (MH+), C₂₉H₁₈F₆N₂ _(O) ₂=540 g/mol, HPLC purity=90%.

[0580] 5.1.2.137 Synthesis of4-{`-[1,3-dimethyl-5-(nitromethyl)pyrazol-4-yl]-5-(4-hydroxyphen)-4-phenylpyrazol-3-yl }phenol

[0581] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 3-dimethyl-5-nitropyrazole-4-ylhydrazinewas used to form the pyrazole heterocycle.

[0582] ESMS m/z 482 (MH⁺), C₂₇H₂ ₂₃N₅O₄=481 g/mol, HPLC purity=90%.

[0583] 5.1.2.138 Synthesis of4-{1-[5-chloro-3-(trifluoromethyl)(2-pyridyl)-5-(4-hydroxyphenyl)-4-phenypyrazol-3-yl}phenol

[0584] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2,5-chloro-3-trifluoromethyl-2-pyridylhydrazine was used to form thepyrazole heterocycle.

[0585] ESMS m/z 508 (MH⁺), C₂₇H₁₇ClF₃N₃O₂=507 g/mol, HPLC purity=90%.5.1.2.139 Synthesis of4-{1-[3-chloro-5-(trifluoromethyl)(2-pyridyl)]-5-(4-hydroxypheny)-4-phenylpyrazol-3-yl}phenol

[0586] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2,3-chloro-5-trifluoromethyl-2-pyridylhydrazine was used to form thepyrazole heterocycle.

[0587] ESMS m/z 508 (MH⁺), C₂₇H₁₇ClF₃N₃O₂=507 g/mol, HPLC purity=90%.

[0588] 5.1.2.140 Synthesis of4-[5-(4-hydroxyphenyl)-4-phenyl-1-(1,3,4-trimethylpyrazolo[4,5-e]pyridin-6-yl)pyrazol-3-yl]phenol

[0589] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 1,3,4-trimethylpyrazolo[5,4-b]pyridine-6-ylhydrazine was used to form the pyrazole heterocycle.

[0590] ESMS m/z 488 (MH⁺), C₃₀H₂N₅O₂=487 g/mol, HPLC purity=90%.

[0591] 5.1.2.141 Synthesis of4-[3-(4-hydroxyphenyl)-1-(6-methylpyridazin-3-yl)-4-phenylpyrazol-5-yl]phenol

[0592] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 6-methylpyridazine-3-ylhydrazine was usedto form the pyrazole heterocycle.

[0593] ESMS ln/z 421 (MM ), C₂₆H₂₀N₄O₂ =420 g/mol, HPLC purity =90%.

[0594] 5.1.2.142 Synthesis of 4-[1-(6-chloro-2-fluorophenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol

[0595] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 6-chloro-2-fluorophenyl hydrazine was usedto form the pyrazole heterocycle.

[0596] ESMS m/z 457 (MH⁺), C₂₇H₈ClFN₂O₂=456 g/mol, HPLC purity=90%.

[0597] 5.1.2.143 Synthesis of4-[1,3-bis(4-hydroxyphenyl)-4-ethylpyrazol-5-yl]phenol

[0598] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2,4-methoxyphenyl hydrazine was used to formthe pyrazole heterocycle.

[0599] ESMS m/z 373 (MH⁺), C₂₃H₂₀N₂O₃=372 g/mol, HPLC purity=90%.

[0600] 5.1.2.144 Synthesis of4-[1,3-bis(4-hydroxyphenyl)-4-phenylpyrazol-5-yl]phenol

[0601] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, 4-methoxyphenyl hydrazine was used to formthe pyrazole heterocycle.

[0602] ESMS m/z 421 (MH⁺), C₂₇H₂₀N₂O₃=420 g/mol, HPLC purity=90%.

[0603] 5.1.2.145 Synthesis of4-[1,3,5-tis(4-hydroxyphenyl)pyrazol-4-yl]phenol

[0604] This compound was synthesized in the same manner as described inSection 5.1.2.6. In step 2, 4-methoxyphenyl hydrazine was used to formthe pyrazole heterocycle.

[0605] ESMS m/z 437 (MH⁺), C₂₇H₂₀N₂O₄=436 g/mol, HPLC purity=90%.

[0606] 5.1.2.146 Synthesis of4-[1,3-bis(4-hydroxyphenyl)pyrazol-5-yl]phenol

[0607] This compound was synthesized following procedures described inScheme 1.

[0608] Step 1: To a solution of 4′-methoxyacetophenone (1.0 equiv.) inTHF at−78° C. was added dropwise 1.5 equiv. of [(CH₃)₂Si]₂NLi. Thesolution was stirred for 1 h at −78° C., followed by addition of 1.2equiv. of p-anisoyl chloride. The reaction mixture was stirred for 10min at −78° C. and then for 22 h at rt, acidified with 10% citric acid,and extracted with EtOAc. The combined organic layers were washed withwater and dried over Na₂SO₄. Removal of solvent in vacuo provided acrude solid which was purified by flash chromatography (CH₂Cl₂) to give1,3-di(4- methoxyphenyl) propane-1,3-dione.

[0609] Step 2: A mixture of the 1,3-diketone obtained in step 1 (1.0equiv.), 4-methoxyphenyl hydrazine (1.5 equiv.), conc. HCl aq.(catalytic amount) and ethanol was heated to reflux overnight. Cooled tort and removed solvent in vacuo. Water and ethyl acetate were added. Theorganic layer was separated, washed with dil. HCl, brine, dried,filtered and the solvent was concentrated in vacuo to give the product1-[1,5-bis(4-methoxyphenyl)pyrazol-3-yl]-4-methoxybenzene.

[0610] Step 3: Demethylation was performned as described in Scheme 1 toafford the final product.

[0611] ESMS m/z 345 (MH⁺), C₂₁H₁₆N₂O₃=344 g/mol, HPLC purity=90%.

[0612] 5.1.2.147 Synthesis of4-[4-ethyl-5-(4-hydroxyphenyl)-1-methylpyrazoi-3-yl]phenol

[0613] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, methylhydrazine was used to form thepyrazole heterocycle.

[0614] ESMS m/z 295 (MH⁺), C18H₁₈N₂O₂=294 g/mol, HPLC purity=98%.

[0615] 5.1.2.148 Synthesis of4-[4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol

[0616] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, hydrazine was used to form the pyrazoleheterocycle.

[0617] 5.1.2.149 Synthesis of3-(4-hydroxyphenyl)-2,4,5-trihydrobenzo[g]1H-indazol-7-ol

[0618] This compound was synthesized based upon Scheme 1.

[0619] Step 1: To a solution of 6-methoxy-1-tetralone (1.0 equiv.) inTHF at −78° C. was added dropwise 1.5 equiv. of [(CH₃)₂Si]₂ NLi. Thesolution was stirred for 1 h at −78° C., followed by addition of 1.2equiv. of p-anisoyl chloride. The reaction mixture was stirred for 10min at −78° C. and then for 22 h at rt, acidified with 10% citric acid,and extracted with EtOAc. The combined organic layers were washed withwater and dried over Na₂SO₄. Removal of solvent in vacuo provided acrude solid which was purified by flash chromatography (CH₂Cl₂) to give6-methoxy-2-[(4-methoxyphenyl) carbonyl]-2,3,4-trihydronaphthalen-1-one.

[0620] Step 2: A mixture of the 1,3-dilketone obtained in step 1 (1.0equiv.), hydrazine (1.5 equiv.), conc. HCl aq. (catalytic amount) andethanol was heated to reflux overnight. Cooled to rt and removed solventin vacuo. Water and ethyl acetate were added. The organic layer wasseparated, washed with dil. HCl, brine, dried, filtered and the solventwas concentrated in vacuo to give the pyrazole product.

[0621] Step 3: Demethylation was performed as described in Scheme 1 toafford the final product.

[0622] ESMS m/z 279 (MH⁺), C₁₇H₁₄N₂O₂=278 g/mol; HPLC purity=85%.

[0623] 5.1.2.150 Synthesis of3-(4-hydroxyphenyl)-2-methyl-2,4,5-trihydrobenzo[g]1H-indazol-7-ol

[0624] This compound was synthesized in the same manner as described inSection 5.1.2.149. In step 2, methylhydrazine was used to form thepyrazole heterocycle.

[0625] ESMS m/z 293 (MH⁺), C₁₈H₁₆N₂O₂=292 g/mol; HPLC purity=85%.

[0626] 5.1.2.151 Synthesis of3-(4-hydroxyphenyl)-2-phenyl-2,4,5-trihydrobenzo[g]1H-indazol-7-ol

[0627] This compound was synthesized in the same manner described inSection 5.1.2.149. In step 2, phenylhydrazine was used to form thepyrazole heterocycle.

[0628] ESMS m/z 355 (MH⁺), C₂₃H₁₈N₂O₂=354 g/mol; HPLC purity=85%.

[0629] 5.1.2.152 Synthesis of 1-[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazoyl]-4-(methylsulfonyl)benzene

[0630] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, 4-methylsulfonylphenylhydrazine was used toform the pyrazole heterocycle.

[0631]¹H NMR (MeOH-d₄):δ0.88 (3H, t, J=7.3 Hz), 2.51 (2H, q, J=7.2 Hz),3.20 (3H, s), 6.75 (2H, d, J=8.6 Hz), 6.79 (2H, d, J=8.6 Hz), 7.00 (2H,d, J=8.8 Hz), 7.41 (2H, d, J=8.6 Hz), 7.45 (2H, d, J=8.8 Hz), 7.77 (2H,d, J=8.6 Hz); ESMS m/z 435 (MH⁺), C₂₄H₂₂N₂O₄S=434 g/mol; HPLCpurity=91.4%.

[0632] 5.1.2.153 Synthesis of3-{[3,5-bis(4-hydroxyphenyl)pyrazolyl]methyl}phenol

[0633] This compound was synthesized based upon Scheme 4.

[0634] Step 1: Same as Step 1 in Section 5.1.2.149.

[0635] Step 2: Same as Step 2 in Section 5.1.2.149 but using hydrazineto form pyrazole ring.

[0636] Step 3: Alkylation. Similar as step 3 in Section 5.1.2.41 using3′-methoxybenzyl chloride as alkylating agent.

[0637] Step 4: Step 3: Demethylation was performed as described inScheme 1 to afford the final product. ¹H NMR (Acetone-d6): δ 0 5.24 (2H,s), 6.55 (2H, d, J=8.6 Hz), 6.56 (1H, s), 6.64 (1H, d, J=6.6 Hz), 6.81(2H, d, J=8.4 Hz), 6.84 (2H, d, J=8.9 Hz), 7.05 (1H, t, J=8.6 Hz), 7.21(2H, d, J=8.2 Hz), 7.68 (2H, d, J=8.2 Hz); ESMS m/z 359 (MH⁺),C₂₂H₁₈N₂O₃=358 g/mol; HPLC purity =83.8%.

[0638] 5.1.2.154 Synthesis of1-[3,5-bis(4-hydroxyphenyl)-4-methylpyrazolyl]-4-(methylsulfonyl)benzene

[0639] This compound was synthesized based upon Scheme 1.

[0640] Step 1: To a solution of 4′-methoxypropylphenone (1.0 equiv.) inTHF at −78° C. was added dropwise 1.5 equiv. of [(CH₃)₂Si]₂NLi. Thesolution was stirred for 1 h at −78° C., followed by addition of 1.2equiv. o fp-anisoyl chloride. The reaction mixture was stirred for 10min at −78° C. and then for 22 h at rt, acidified with 10% citric acid,and extracted with EtOAc. The combined organic layers were washed withwater and dried over Na₂SO₄. Removal of solvent in vacuo provided acrude solid which was purified by flash chromatography (CH₂C1₂) to give1,3-di(4-methoxyphenyl)- 2-methyl-propane- 1,3-dione.

[0641] Step 2: A mixture of the 1,3-diketone obtained in step 1 (1.0equiv.), 4-methylsulfonylphenyl hydrazine (1.5 equiv.), conc. HCl aq.(catalytic amount) and ethanol was heated to reflux overnight. Cooled tort and removed solvent in vacuo. Water and ethyl acetate were added. Theorganic layer was separated, washed with dil. HCl, brine, dried,filtered and the solvent was concentrated in vacuo to give the pyrazoleproduct.

[0642] Step 3: Demethylation was performed as described in Scheme 1 toafford the fmial product.

[0643] ESMS m/z 421 (MH⁺), C₂₃H₂₀N₂O₄S=420 g/mol; HPLC purity =85%.

[0644] 5.1.2.155 Synthesis of1-[3,5-bis(4-hydroxyphenyl)pyrazolyl]-4-(methylsulfonyl)benzene

[0645] This compound was synthesized in the same manner as described inSection 5.1.2.146. In step 2, 4-methylsulfonylphenylhydrazine was usedto form the pyrazole heterocycle. ¹H NMR (Methanol-d₄): δ 2.04 (3H, s),6.68 (2H, d, J=8.9 Hz), 6.69 (1H, s), 6.74 (2H, d, J=8.8 Hz), 7.03 (2H,d, J=8.8 Hz), 7.48 (2H, d, J=8.9 Hz), 7.63 (2H, d, J=8.8 Hz), 7.85 (2H,d, J=8.8 Hz); ESMS m/z 407 (MH⁺), C₂₂H₁₈N₂O₄S=406 g/mol; HPLCpurity=86.4%.

[0646] 5.1.2.156 Synthesis of3-{[3,5-bis(4-hydroxyphenyl)-4-methylpyrazolyl]methyl}phenol

[0647] This compound was synthesized based upon Scheme 4.

[0648] Step 1: Same as step I in Section 5.1.2.154.

[0649] Step 2: Similar as step 2 in Section 5.1.2.154 but usinghydrazine to form pyrazole ring.

[0650] Step 3: Alkylation. Same as step 3 in example 51623 using3′-methoxybenzyl bromide as alkylating agent.

[0651] Step 4: Demethylation was performed as described in Scheme 1 toafford the final product.

[0652]¹H NMR (methanol-d₄): δ 1.97 (3H, s), 5.07 (2H, s), 6.44 (1H, d,J=7.3 Hz), 6.50 (1H, s), 6.58 (1H, dd, J=8.2 Hz, 2.6 Hz), 6.81 (2H, d,J=8.6 Hz), 6.85 (2H, d, J=8.6 Hz), 6.98 (1H, t, J=7.9 Hz), 7.05 (2H, d,J=8.6 Hz), 7.53 (2H, d, J=8.8 Hz); ESMS m/z 372 (MH⁺), C₂₃H₂₀N₂O₃=372g/mol; HPLC purity=95.0%.

[0653] 5.1.2.157 Synthesis of3-{[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]methyl}phenol

[0654] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, 3′-methoxybenzyl chloride was used asalkylating agent.

[0655]¹H NMR (acetone-d₆): δ 0.95 (3H, t, J=7.5 Hz), 2.53 (2H, d, J=7.5Hz), 5.08 (2H, s), 6.48 (1H, d, J=8.2 Hz), 6.56 (1H, m), 6.65 (1H, dd,J=8.8 Hz, 3.6 Hz), 6.87 (2H, d, J=8.8 Hz), 6.91 (2H, d, J=8.8 Hz), 7.04(1H, t, J=7.8 Hz), 7.11 (2H, d, J=8.6 Hz), 7.57 (2H, d, J=8.8 Hz); ESMSm/z 386 (MH⁺), C₂₄H₂₂N₂O₃=386 g/mol; HPLC purity =96.5%.

[0656] 5.1.2.158 Synthesis of8-[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]-N-butyl-N-methyloctanamide

[0657] This compound was synthesized based upon Scheme 4.

[0658] Step 1 and 2: Same as corresponding steps in Section 5.1.2.88.

[0659] Step 3: Preparation of the alkyl halide8-bromo-N-butyl-N-methyloctanamide. Using oven dried glassware under aninert atmosphere isobutylchloroformnate (0.64 mL) was added dropwise to8-bromooctanoic acid (1.00 g) and NMM (0.74 mL) in THF (10 mL) at −23 °C. The solution was stirred for 3 minutes then N-methylbutylamine (0.8mL) in THF (5 mL) was added. The solution was stirred at −23° C. for 30minutes then at room temperature overnight. EtOAc (25 mL) added and thesolution washed with 2 M HCl (2 ×25 mL), NaHCO₃ solution (2 ×25 mL) andbrine (25 mL). It was then dried (Na₂SO₄) and the solvent removed togive the product as a light yellow oil (1.60 g) which was used withoutfurther purification. ESMS m/z 292 (MH⁺), C₁₃H₂₆BrNO=291 g/mol.

[0660] Step 4: Alkylation. Unalkylated pyrazole (obtained from step 2,1.0 equiv.) and alkyl bromide (obtained from step 3, 2.0 equiv.) weredissolved in DMF then Cs₂CO₃ (2.0 equiv.) added. The mixture was stirredat 100° C. overnight then EtOAc added. The solution was washed with 10%citric acid solution (2×), NaHCO₃ solution (2×), and brine, dried(Na₂SO₄) and the solvent removed to give a yellow solid. The crudeproduct was purified by flash chromatography (50% EtOAc/petrol) to givea colourless oil (yield =40%).

[0661] Step 5: Demethylation was performed as described in Scheme Itoafford the final product.

[0662]¹H NMR (CDCI₃): δ 0.72-0.81 (2H, m), 0.82-0.91 (6H, m), 0.93-1.62(12H, m), 2.14-2.20 (2H, m), 2.43 (2H, q, J=7.5 Hz), 2.86 (1.5H, s),2.89 (1.5H, s), 3.17 (1H, t, J=7.5 Hz), 3.31 (1H, t, J=7.5 Hz), 3.91(2H, t, J=7.1 Hz), 6.78 (2H, d, J=8.6 Hz), 6.89 (2H, d, J=8.4 Hz), 7.08(2H, d, J=8.8 Hz), 7.45 (2H, d, J=8.6 Hz); ESMS m/z 492 (MH⁺),C₃₀H₄₁N₃O₃=491 g/mol; HPLC purity=99.0%.

[0663] 5.1.2.159 Synthesis of3-(4-hydroxyphenyi)-2-methylindeno[3,2-c]pyrazol-6-ol

[0664] This compound was synthesized in the same manner as described inSection 5.1.2.150. In step 1, 5-methoxy-1-indanone and p-anisoylchloride were used as starting materials.

[0665] ESMS m/z 279 (MH⁺), C₁₇H₁₄N₂O₂=278 g/mol; HPLC purity=95%.

[0666] 5.1.2.160 Synthesis of 1-[1-cyclobutyl-4-ethyl-5-(4-methoxyphenyl)pyrazol-3-yl]-4-methoxybenzene

[0667] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, chlorobutane was used as alkylating agent.Step 4 was not performed.

[0668]¹H NMR (CDCI₃): δ 0.93 (3H,, J=7.4 Hz), 1.59-1.67 (2H, m), 1.83(2H, q, J=10.1 Hz), 2.19-2.26 (2H, m), 2.47 (2H, q, J=7.5 Hz), 3.83 (3H,s), 3.87 (3H, s), 6.96 (2H, d, J=8.6 Hz), 7.00 (2H, d, J=8.6 Hz), 7.21(2H, d, 8.6 Hz), 7.65 (2H, d, J=8.6 Hz); ESMS m/z 363 (MH⁺),C₂₃H₂₆N₂O₂=362 g/mol; HPLC purity=91.2%.

[0669] 5.1.2.161 Synthesis of4-[1,4diethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol

[0670] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, chloroethane was used as alkylating agent.

[0671]¹H NMR (MeOH-d₄): δ 0.77 (3H, t, J=7.4 Hz), 1.24 (3H, t, J=7.1Hz), 2.42 (2H, q, J=7.5 Hz), 3.95 (2H, q, J=7.1 Hz), 6.82 (2H, d, J=8.4Hz), 6.89 (2H, d, J=8.4 Hz), 7.15 (2H, d, J=8.4 Hz), 7.38 (2H, d, J=8.4Hz); ESMS m/z 309 (MH+), C_(l9)H₂₀N₂O₂=308 g/mol; HPLC purity=89.3%.

[0672] 5.1.2.162 Synthesis of4-[4ethyl-5-(4-hydroxyphenyl)-1-propylpyrazol-3-yl]phenol

[0673] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, 1-chloropeopane was used as alkylatingagent.

[0674]¹H NMR (MeOH-d₄): δ 0.77 (3H, t, J=7.3 Hz), 0.89 (3H, t, J=7.3Hz), 1.69 (2H, q, J=7.3 Hz), 2.44 (2H, q, J=7.3 Hz), 3.90 (2H, t, J=7.3Hz), 6.84 (2H, d, J=8.1 Hz), 6.91 (2H, d, J=8.1 Hz), 7.16 (2H, d, J=8.2Hz), 7.4 (2H, d, J=8.2 Hz); ESMS m/z 323 (MH+), C₂₀H₂₂N₂O₂=322 g/mol;HPLC purity=88.5%.

[0675] 5.1.2.163 Synthesis of4-[1-butyl-4ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol

[0676] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, 1-chlorobutane was used as alkylatingagent.

[0677]¹H NMR (Acetone-d₆): δ 0.71 (3H, t, J=7.23 Hz), 0.86 (3H, t, J=7.5Hz), 1.11 (2H, t, J=7.5 Hz), 1.61 (2H, t, J=7.23 Hz), 2.41 (2H, t,J=7.43 Hz), 3.85 (2H, t, J=7.23 Hz), 6.80 (2H, d, J=8.79 Hz), 6.91 (2H,d, J=8.59 Hz), 7.13 (2H, d, J=8.59 Hz), 7.48 (2H,d, J=8.79 Hz), 8.21(1H, s), 8.55 (1H, s); ESMS m/z 337 (MH+), C₂₁H₂₄N₂O₂=336 g/mol; HPLCpurity=81.1%.

[0678] 5.1.2.164 Synthesis of4-[4-ethyl-5-(4-hydroxyphenyl)-1-(2-methylpropyl)pyrazol-3-yl]phenol

[0679] This compound was synthesized in the same manner described inSection 5.1.2.88.In step 3, 1-chloro-2-methylpropane was used asalkylating agent.

[0680]¹H NMR (Acetone-d₆): δ 0.73 (6H, d, J=7.51 Hz), 0.93 (3H, t, J=7.5Hz), 2.01 (1H, m), 2.08 (1H, m), 2.49 (2H, q, J=7.51 Hz), 3.72 (2H, d,J=7.33 Hz), 6.86 (2H, d, J=8.79 Hz), 6.96 (2H, d, J=7.9 Hz), 7.18 (2H,d, J=8.0 Hz), 7.54 (2H, d, J=8.2 Hz); ESMS m/z 337 (MH+), C₂₁H₂₄N₂O₂=336g/mol; HPLC purity=96.0%. 5.1.2.165 Synthesis of4-[4-ethyl-5(4-hydroxyphenyl)-1 -prop2-enylpyrazol-3-yl]phenol

[0681] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, allyl bromide was used as alkylating agent.

[0682]¹H NMR (MeOH-d₄):δ0.90 (3H, t, J=7.5 Hz), 2.46 (2H, q, J=7.5 Hz),4.55 (2H, d, J=4.9 Hz), 4.79 (1H, d, J=17.2 Hz), 5.01 (1H, d, J=10.41Hz), 5.85-5.78 (1H, m), 6.76 (2H, d, J=8.4 Hz), 6.81 (2H, d, J=8.41 Hz),7.08 (2H, d, J=8.4 Hz), 7.32 (2H, d, J=8.4 Hz); ESMS m/z 321 (MH+),C₂₀H₂₀N₂O₂=320 g/mol; HPLC purity=91.2%. 5.1.2.166 Synthesis of 4-[1-(cyclohexylmethy)-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol

[0683] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, chlorocyclohexylmethane was used asalkylating agent.

[0684]¹H NMR (Acetone-d6):δ0.92 (3H, t, J=7.33 Hz), 1.07-1.11 (3H, m),1.51-1.62 (3H, m), 1.77-1.80 (1H, m), 2.49 (2H, q, J=7.51 Hz), 3.74 (2H,d, J=7.06 Hz), 6.86 (2H, d, J=8.79 Hz), 6.97 (2H, d, J=8.79 Hz), 7.17(2H, d, J=8.61 Hz), 7.54 (2H, d, J=8.79 Hz); ESMS m/z 377 (MH⁺),C₂₄H₂8N₂0₂=376 g/mol; HPLC purity =96.1%.

[0685] 5.1.2.167 Synthesis of4-[1-cyclobutyl-4ethyl-5-(4-hydroxyphenl)pyrazol-3-yllphenol

[0686] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, chlorobutane was used as alkylating agent.

[0687]¹H NMR (Acetone-d6):δ0.92 (3H, t, J=7.33 Hz), 1.67-1.77 (2H, m),2.16-2.22 (2H, m), 2.48 (2H, q, J=7.33 Hz), 2.67 (2H, m), 4.544.58 (1H,m), 6.88 (2H, d, J=8.79 Hz), 6.97 (2H, d, J=8.61 Hz), 7.15 (2H, d,J=8.61 Hz), 7.57 (2H, d, J=8.79 Hz), 8.27 (1H, s), 8.61 (1H, s); ESMSn/z 335 (MH⁺), C₂lH₂₂N₂0₂=334 g/mol; HPLC purity =89.6%.

[0688] 5.1.2.168 Synthesis of 4-[l-cyclohexyl4-ethyl-5-(4-hydroxyphenyl)pyrazol-3yl]phenol

[0689] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, chlorohexane was used as alkylating agent.

[0690]¹H NMR (Acetone-d6): 8 0.92 (3H, t, J=7.33 Hz), 1.09-1.20 (3H, m),1.59 (1H, s), 1.76-1.82 (4H, m), 1.93-1.97 (2H, m), 2.48 (2H, q, J=7.43Hz), 3.83-3.89 (1H, m), 6.86 (2H, d, J=8.79 Hz), 6.97 (2H, d, J=8.60Hz), 7.18 (2H, d, J=8.60 Hz), 7.54 (2H, d, J=8.60 Hz), 8.24 (1H, s),8.60 (1H, s); ESMS m/z 363 (MH⁺), C₂₃H₂₆N₂0₂=362 g/mol; HPLC purity=96.9%.

[0691] 5.1.2.169 Synthesis of4-14-ethy-5-(4-hydroxypheny)-I-(2-morpholin-4-yethy)pyrazol-3-Aphenol

[0692] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, N-(2- chloroethyl)morpholine was used asalkylating agent.

[0693]¹H NMR (Acetone-d6): o 0.86 (3H, t, J=7.51 Hz), 2.42 (2H, q,J=7.51 Hz), 2.61-2.78 (4H, m), 3.21 (4H, m), 4.03 (2H, t, J=7.51 Hz),6.80 (2H, d, J=8.79 Hz), 6.89 (2H, d, J=8.61 Hz), 7.19 (2H, d, J=8.61Hz), 7.43 (2H, d, J=8.79 Hz); ESMS mJZ 394 (MH⁺), C2H₂₇N₃0₃=393 g/mol;HPLC purity =91.8%.

[0694] 5.1.2.170 Synthesis of2-[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazoll]acetamide

[0695] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, 2-chloroacetamidewas used as allylatingagent.

[0696]¹H NMR (MeOH-d4): o 0.93 (3H, t, J=7.4 Hz), 2.50 (2H, q, J=7.4Hz), 4.6 (2H, s), 6.84 (2H, d, J=8.4 Hz), 6.89 (2H, d, J=8.2 Hz), 7.21(2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.2 Hz); ESMS m/z 338 (MH⁺),Cl₉Hl₉N₃0₃=337 g/mol; HPLC purity =94.5%.

[0697] 5.1.2.171 Synthesis of1-[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]acetone

[0698] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, chloroacetone was used as alkylating agent.

[0699]¹H NMR (Acetone-d6): 50.95 (3H, t, J=7.43 Hz), 1.98 (3H, s), 2.52(2H, q, J=7.62 Hz), 7.76 (2H, s), 6.88 (2H, d, J=8.79 Hz), 6.94 (2H, d,J=8.79 Hz), 7.16 (2H, d, J=8.79 Hz), 7.54 (2H, d, J=8.60 Hz), 8.31 (1H,s), 8.64 (1H, s); ESMS zn/z 337 (MH⁺), C₂OH₂₀N₂0₃=336 g/mol; HPLC purity=85.5%.

[0700] 5.1.2.172 Synthesis of4-[1lyclopentyl4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol

[0701] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, chloropentane was used as alkylating agent.

[0702]¹H NMR (Acetone-d6): 6 0.82 (3H, t, J=7.43 Hz), 1.46 (3H, d,J=7.62 Hz), 2.38 (2H, q, J=7.43 Hz), 4.35 (2H, s), 5.24-5.31 (1H, m),5.40-5.47 (1H, m), 6.76 (2H, d, J=8.60 Hz), 6.84 (2H, d, J=8.40 Hz),7.08 (2H, d, J=8.60 Hz), 7.43 (2H, d, J=8.60 Hz), 8.17 (1H, s), 8.50(1H, s); ESMS ,nz 349 (MH⁺), C₂₂H₂₄N₂0₂=348 g/mol; HPLC purity =98.7%.5.1.2.173 Synthesis of4-[4-ethyl-5-(4-hydroxyphenyl)-1-(methylethyl)pyrazol-3-yl]phenol

[0703] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, 2-chloropropane was used as alkylatingagent.

[0704]¹H NMR (Acetone-d₆): δ0.93 (3H1, t, J=7.5 Hz), 1.41 (6H, d, J=6.78Hz), 2.48 (2H, q, J=7.5 Hz), 4.344.37 (1H, m), 6.89 (2H, d,J=8.6 Hz),6.99 (2H, d, J=8.8 Hz), 7.22 (2H, d, J=8.6 Hz), 7.59 (2H, d, J=8.8 Hz);ESMS m/z 323 (MH⁺), C₂₀H₂₂N₂0₂=322 g/mol; HPLC purity =83.8%.

[0705] 5.1.2.174 Synthesis of4-[Iycloheptyl4-ethyl-5-(4-hydroxyphenyA)pyrazol-3yllphenol

[0706] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, chlorocycloheptane was used as alkylatingagent.

[0707]¹H NMR (Acetone-d6): 8 0.92 (3H, t, 3=7.43 Hz), 1.16-1.25 (3H, m),1.43 (4H, s), 1.64 (2H, m), 1.76 (2H, m), 2.02 (1H, m), 2.39 (2H, m),3.97-3.99 (1H, m), 6.76 (2H, d, J=8.60 Hz), 6.87 (2H, d, J=8.40 Hz),7.07 (2H, d, J=8.60 Hz), 7.45 (2H, d, J=8.60 Hz), 8.14 (1H, s), 8.51(1H, s); ESMS m/z 377 (MH⁺), C₂₄H2₈N₂0₂=376 glmol; HPLC purity =97.9%.

[0708] 5.1.2.175 Synthesis of4-[1-(cyclopropylmethyl)-4-ethyl-5-(4-hydroxyphenyi)pyrazol-3-yl]phenol

[0709] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, chlorocyclopropylmethane was used asalkylating agent.

[0710]¹H NMR (Acetone-4): 8 0.82 (3H, t, J=7.4 Hz), 1.46 (3H, d, J=7.6Hz), 2.38 (2H, q, J=7.4 Hz), 4.35 (2H, s), 5.24-5.31(1H, m), 5.40-5.47(1H, m), 6.76(2H, d, J=8.6 Hz), 6.84 (2H, d, J=8.4 Hz), 7.08(2H, d,J=8.6 Hz), 7.43 (2H, d, 3=8.6 Hz), 8.17 (1H, s), 8.50 (1H, s); ESMS: m/z335 (MH⁺), C₂lH22N₂0₂=334 g/mol; HPLC purity =87.3%. 5.1.2.176 Synthesisof 3-(4-hydroxyphenyl)-1-rmethylindeno[2,3-d]pyrazol-60o

[0711] This compound is the regioisomer of the compound made in Section5.1.2.159. The synthesis is identical. HPLC was used to isolate the twoisomers. ESMS n/z 279 (MH⁺), C₁7Hl₄N₂0₂=278g/mol; HPLC purity =90%.

[0712] 5.1.2.177 Synthesis of4-14-ethyl-5-(4-hydroxyphenyl)-1-phenylpyrazol-3y(]phenol

[0713] This compound was synthesized in the same manner described inSection 5.1.2.46. In step 2, phenyl hydrazine was used as the reagent toform pyrazole. ESMS m/z 357 (MH), C₂₃H2oN₂0₂ =356 glmol, HPLC purity=90%.

[0714] 5.1.2.178 Synthesis of4-[5-(4-hydroxyphenyl)-1,4iphenylpyrazol-3-y]phenot

[0715] This compound was synthesized in the same manner described inSection 5.1.2.105. In step 2, phenyl hydrazine was used as the reagentto form pyrazole.

[0716] ESMS m/z 405 (MH⁺), C₂₇H₂₀N₂0₂=404 gimol, HPLC purity =90%.

[0717] 5.1.2.179 Synthesis of244-ethp-5-(4-hydroxypheny)-I-[2-(tdfluoromethyl)phenyl]pyrazol-3-yiphenol

[0718] This compound was synthesized based upon Scheme 1.

[0719] The procedures are same as described in Section 5.1.2.53. In stepI, 4′-methyxobutyrylphenone and σ-anisoyl chloride were used as startingmaterials.

[0720] ESMS m/z 425 (MH⁺), C₂₄Hl₉F₃N₂0₂ =424 g/mol, HPLC purity =90%.

[0721] 5.1.2.180 Synthesis of 34-ethy-5(4-hydroxypheny)-12-(trifluoromethy)phenyllpyrazol-3-yllphenol

[0722] The procedures are same as described in Section 5.1.2.53. In stepI, 4′-methyxobutyrylphenone and σ-anisoyl chloride were used as startingmaterials.

[0723] ESMS m/z 425 (MH⁺), C₂₄Hl₉F₃N₂0₂ =424 g/mol, HPLC purity =90%.

[0724] 5.1 .2.181 Synthesis of3-11-(4-hydroxyphenyl)-3-(3-hydroxyphenyl)4-methylpyrazol-5-yq]phenol

[0725] This compound was synthesized based upon Scheme I and Scheme 3.

[0726] Step 1: Formation of 1,3-diketone. Same as Step I in Section5.1.2.6 using 3′-methyxobutyrylphenone and σ-anisoyl chloride were usedas starting materials.

[0727] Step 2: Alkylation. A THF solution of the above 1,3-diketone (1.0equiv.) was added dropwise to a suspension of sodium hydride (1.1 eq) inTHF at 0° C. The mixture was stirred at rt for 30 min. followed byaddition of iodomethane (1.1 equiv.). The reaction mixture was stirredat rt overnight, poured into saturated NH4CI aq. and extracted withether and DCM. The organic extracts were washed with brine, dried withMgSO₄ and concentrated in vacuo to give the product1,3-bis(3-methoxyphenyl)-2-methylpropane-1,3-dione.

[0728] Step 3: Same as step 2 in Section 5.1.2.6. 4-methoxyphenylhydrazine was used to form the pyrazole core.

[0729] Step 4: Demethylation was performed as described in Scheme I toafford the final product. ESMS m/z 359 (MH⁺), C22HIEN20₃ =358 g/mol,HPLC purity =90%. 5.1.2.182 Synthesis of3-1[(3hydroxyphenyl)4-methyl-1-phenylpyrazol-5-yl]phenol

[0730] This compound was synthesized in the same manner as described inSection 5.1.2.18 1. In step 3, phenyl hydrazine was used to form thepyrazole core.

[0731] ESMS m/z 343 (MH), C₂₂HR,N₂0₂ =342 g/mol, HPLC purity =90%.5.1.2.183 Synthesis of3,5bis(4-hydroxyphenyl)-4-ethyl--(methylsulfonyl)pyrazole

[0732] This compound was synthesized based upon Scheme 4.

[0733] Steps 1 and 2: Same as corresponding steps in Section 5.1.2.148.

[0734] Step 3: Sulfonylation. To a solution of methanesulfonyl chloride(2.0 equiv.) and dry pyridine (solvent) in a screw cap container wasadded the pyrazole (1.0 equiv., obtained from step 2). After dissolutionby shaking, the resultant solution was heated in a sealed tube at 60-65°C. for 22.5h. The solution obtained was concentrated in vacuo and theresidue partitioned between ethyl acetate and water. The organic phasewas separated, washed with 7% NaHCO₃ (2 x), brine (2 ×), then dried(Na₂SO₄) and the solvent removed to give a dark brown oil.Crystallisation was induced by the addition of pet. spirits (40-60°, ca.3 mL) and the solid obtained was ground, collected, then washed withcold ether (2×0.5mL) and dried overnight in vacuo to give thesulfonamide as a brown powder (yield =33%).

[0735] Note that in some cases EtOAc/pet. Spirits were used forrecrystallization.

[0736] Step 4: Demethylation. A solution of the above sulfonamide (1.0equiv.) in dry DCM was treated with AIC1₃ (6.0 equiv.) and ethane thiol(6.0 equiv.) and stirred in a sealed container for 16h. The reactionmixture was diluted with stOAc and washed with 10% citric acid solution(2 ×), 7% NaHCO₃ (2 x), brine, then dried (Na₂SO₄) and concentrated invacuo to give a residue which was purified by flash columnchromatography (EtOAc: pet. spirits 2: 1) to afford product as anoff-white solid (yield =43%).

[0737]¹H NMR (D₆-DMSO): 8 0.87 (3H, t, .7.4 Hz, 2.39 (2H, q, J=7.5 Hz),3.37 (3H, s), 6.84 (2H, d, #8.4 Hz), 6.88 (2H, d, J=8.6 Hz), 7.22 (2H,d, J=8.4 Hz), 7.54 (2H, d, #8.6 Hz), 9.70 (1H, s), 9.72 (1H, s); ESMS:m/z 359 (MH⁺), C18Hl₈N₂0₄S =358 g/mol; HPLC purity =96.4%.

[0738] 5.1.2.184 Synthesis of1-113,5bis(4-hydroxyphenyl)-4ethypyrazolyl]sulfonylk2chlorobenzene

[0739] This compound was synthesized in the same manner as described inSection 5.1.2.183. In step 3, 2-chlorophenylsulfonyl chloride was usedto form the sulfonamide.

[0740]¹H NMR (D₆-DMSO): 5 0.84 (3H, t, J7.4 Hz), 2.37 (2H, q, JV7.5 Hz),6.77 (2H, d, J=8.4 Hz), 6.84 (2H, d, J=8.4 Hz), 7.05 (2H, d, J=8.4 Hz),7.41 (2H, d, J=8.6 Hz), 7.50 (1H, t, J=7.5 Hz), 7.70 (3H, m), 9.70 (1H,s), 9.75 (1H, s); ESMS: m/z 455 (MH⁺), C₂₃H₁₉CIN₂0₄S =454 g/mol; HPLCpurity =94.2%.

[0741] 5.1.2.185 Synthesis of3,5-bis(4-hydroxypheny)-4ethyl-1-[(4-methylpheny)sulfonyi]pyrazole

[0742] This compound was synthesized in the same manner as described inSection 5.1.2.183. In step 3,p-toluenesulfonyl chloride was used to formthe sulfonamide.

[0743]¹H NMR (D₆-DMSO): o 0.77 (3H, t, J=7.4 Hz), 2.31 (2H, q, J=7.5Hz), 2.37 (3H, s), 6.85 (4H, m), 7.08 (211, d, J=8.6 Hz,), 7.40 (2H, d,-S8. 1Hz), 7.45 (2H, dd, J6.7, 1.9 Hz), 7.54 (2H, d, J=8.4 Hz); ESMS:m/z 463 (MH⁺), C₂₆H₂₆N₂0₄S =461 g/mol; HPLC purity =94.2%.

[0744] 10 5.1.2.186 Synthesis of3-(4-hydroxyphenyl)-2-methyl-2,4,5-tihydrobenzolg]1H-indazol-6-ol

[0745] This compound was synthesized in the same manner described inSection 5.1.2.149. In step 1, 5-methoxy-1-tetralone was used to form 1,3-diketone. In step 2, methylhydrazine was used to form the pyrazoleheterocycle.

[0746] ESMS nVz 293 (MH⁺), C₁₈1H₆N₂0₂ =292 g/mol, HPLC purity =90%.

[0747] 5.1.2.187 Synthesis of3-(4-hydroxyphenyl)-2-methyl-2,4,5-trihydrobenzo[g)1 H-indazol-8-ol

[0748] This compound was synthesized in the same manner described inSection 5.1.2.149. In step 1, 7-methoxy-1-tetralone was used to form1,3-diketone. In step 2, methylhydrazine was used to form the pyrazoleheterocycle.

[0749] ESMS m/z 293 (MH), C,₈H,lN20₂ =2 g/mol, HPLC purity =90%.

[0750] 1.2.188 Synthesis of(4-hydroxyphenyl)-2-[2-(tdfluoromethyl)phenyl]-2,4,5-trihydrobenzo[g]1H-indazol-8-ol

[0751] This compound was synthesized in the same manner as described inSection 5.1.2.149. In step 2,2-trifluoromethylphenyl hydrazine was usedto form the pyrazole heterocycle.

[0752] ESMS m/z 423 (MH), C₂₄H₁₇F₃N₂0₂ =422 gimol, HPLC purity =90%.

[0753] 5.1.2.189 Synthesis of4-{3-(4-hydroxyphenyl)-1-[2-(trifluoromethyl)phenyl]pyrazol-5-yl}phenol

[0754] This compound was synthesized in the same manner as described inSection 5.1.2.146. In step 2, 2- trifluoromethylphenyl hydrazine wasused to form the pyrazole heterocycle.

[0755] ESMS m/z 397 (Mf), C₂₂H,₅ F₃N₂0₂ =396 gimol, HPLC purity =90%.

[0756] 5.1.2.190 Synthesis of3-(4-hydroxypheny)-2,4,5trihydrobenzo[glH4ndazol6ol

[0757] This compound was synthesized in the same manner described inSection 5.1.2.149. In step 1, 5-methoxy-1-tetralone was used to form1,3-diketone.

[0758] ESMS m/z 279 (MH⁺), C₁₇1H₄N₂0₂ =278 g/mol, HPLC purity =90%.

[0759] 5.1.2.191 Synthesis of4-[1-cyciopropyl4ethy-5-(4-hydroxyphenyl)pyrazol-3-yi]phenol

[0760] This compound was synthesized in the same manner described inSection 5.1.2.88. In step 3, chlorocyclopropane was used for alkylation.

[0761]¹H NMR (DMSO): 8 0.76 (2H, q, J=6.6 Hz), 0.88 (3H, t, J=7.3 Hz),0.93-0.97 (2H, m), 2.42 (2H, q, J=7.5 Hz), 3.38-3.44 (1H, m), 6.79 (2H,d, J=8.8 Hz), 6.89 (2H, d, J=8.6 Hz), 7.25 (2H, d, J=8.4 Hz), 7.39 (2H,d, J=8.6 Hz), 9.39 (1H, s), 9.76 (1H, s); ESMS: n/z 321 (MH⁺),C₂₀H₂₀N₂0₂ =320 g/mol; HPLC purity =80.1%.

[0762] 5.1.2.192 Synthesis of4-(1-{[3,5-bis(4-hydroxyphenyl)4-ethypyrazolylmethyII4-ethy-3-(4-hydroxypheny)pyrazol-5-yl)phenol

[0763] This compound was obtained as a side-product of product describedin Section 5.1.2.191. HPLC was used for isolation.

[0764]¹H NMR (DMSO): o 0.95 (6H, t, J=7.3 Hz), 2.50 (4H, q, J=7.3 Hz),5.93 (2H, s), 6.89 (4H, d, J=8.6 Hz), 6.96 (4H, d, J=8.4 Hz), 7.43 (4H,d, J=8.4 Hz), 7.50 (4H, d, J=8.6 Hz), 9.54 (I1H, s), 9.85 (2H, s); ESMS:nmz 57 (MH⁺), C₃₅H₃₂N₄0₄ =572 g/mol; HPLC purity =85.6%.

[0765] 5.1.2.193 Synthesis of2-cyclobutyl-3-(4-hydroxyphenyl)-2,4,5trihydrobenzo[g]1 H-indazol-6ol

[0766] This compound was synthesized based upon Scheme 4.

[0767] Steps 1 and 2: Same as corresponding steps in Section 5.1.2.190.

[0768] Step 3: Alkylation. Same as step 3 in Section 5.1.2.88 usingchlorocyclobutane as alkylating agent.

[0769] Step 4: Demethylation was performed as described in Scheme I toafford the final product.

[0770] ESMS m/z 333 (MH⁺), C₂,H₂₀N₂0₂ =332 gimol, HPLC purity =90%.

[0771] 5.1.2.194 Synthesis of4-11cyclobutyi-4-ethyl-5-(4-methoxyphenyA)pyrazol-3yl]phenol

[0772] This compound is a derivative of the final product in Section5.1.2.167. To an acetone solution of4-[1-cyclobutyl-4-ethyl-5-(4-hydroxyphenyl) pyrazol-3-yl]phenol (1.0equiv.) was added potassium carbonate (1.0 equiv.) and dimethylsulfate(1.0 equiv.). The mixture was stirred at rt overnight and routinework-up afforded a mixture of starting material, mono-methylated productand di-methylated product. HPLC isolation afforded the title compoundwhich is an off-white powder after lyophilization.

[0773]¹H NMR (DMSO-d6): 5 0.87 (3H, t, J=7.3 Hz), 1.62-1.73 (2H, m),2.14-2.20 (2H, m), 2.41 (2H, q, J=7.5 Hz), 2.56-2.61 (2H, m), 3.82 (3H,s), 4A7-4.51 (1H, m), 6.82 (2H, d, J=8.6 Hz), 7.07 (2H, d, J=8.6 Hz),7.24 (2H, d, J=8.6 Hz), 7.46 (2H, d, J=8.4 Hz), 9.44 (1H, s); ESMS: m/z349 (MH⁺), C₂₂H₂₄N₂0₂ =348 glmol; HPLC purity =98%.

[0774] 5.1.2.195 Synthesis of4-[5(4-acetyloxyphenyl)-1yclobutylAethypyrazol-3-y]phenyl acetate

[0775] This compound is a derivative of the final product in Section5.1.2.167. To a THF solution of4-[1-cyclobutyl4-ethyl-5-(4-hydroxyphenyl) pyrazol-3-yl]phenol was addedacetyl chloride (3.0 equiv.) and pyridine (3.0 equiv.). The mixture wasstirred at rt for 24 h, poured into cold Na3HCO₃, extracted with EtOAc.The organic extracts were washed with beine, dried with NaSO₄ andconcentrated in vacuo. Purification afforded the product as a whitepowder.

[0776]¹H NMR (CDCI₃): o 0.89 (3H, t, J=7.3 Hz), 1.60-1.64 (1H, m),1.65-1.78 (1H, m), 2.14-2.20 (2H, m), 2.25 (3H, s), 2.29 (3H, s), 2.44(2H, q, J=7.5 Hz), 2.69-2.76 (2H, m), 4.46-4.51 (1H, m), 7.09 (2H, d,J=8.6 Hz), 7.15 (2H, d, J=8.6 Hz), 7.25 (2H, d, J=8.6 Hz), 7.66 (2H, d,J=8.8 Hz); ESMS: m/z419 (MH⁺), C1H26N₂0₄ =418 g/mol; HPLC purity =98%.

[0777] 5.1.2.196 Synthesis of4-[5-(4-butanoyloxyphenyl)-1yclobutyl4-ethylpyrazol-3-yllphenylbutanoate

[0778] This compound is a derivative of the final product in Section5.1.2.167. To a THF solutionof4-[1-cyclobutyl-4-ethyl-5-(4-hydroxyphenyl) pyrazol-3-yl]phenol wasadded butyryl chloride (3.0 equiv.) and pyridine (3.0 equiv.). Themixture was stirred at rt for 24 h, poured into cold NaHCO₃, extractedwith EtOAc. The organic extracts were washed with brine, dried withNa₂SO₄ and concentrated in vacuo to give the product as a white powder.

[0779]¹H NMR (CDCI₃): 8 0.89 (3H, t, J=7.5 Hz), 0.99 (3H, t J=7.3 Hz),1.01 (3H, t, J=7.5 Hz), 1.56-1.67 (2H, m), 1.71-1.81 (4H, m), 2.13-2.21(2H, m), 2.43 (2H, q, J=7.5 Hz), 2.50 (2H, t, J=7.3 Hz), 2.52 (2H, t,J=7.3 Hz), 2.68-2.82 (2H, m), 4.434.53 (1H, m) 7.08 (2H, d, J=8.8 Hz),7.15 (2H d, J=8.6 Hz), 7.25 (2H, d J=8.8 Hz), 7.66 (2H, d, J=8.8 Hz);ESMS: m/z 475 (MH⁺), C₂₉H₃₄N₂0₄ =474 g/mol; HPLC purity =98%.

[0780] 5.1.2.197 Synthesis of2-cyclobutyl-3-(4-hydroxphenyl)-2,4,5trihydrobenzolg]1H-indazol-7-0

[0781] This compound was synthesized in the same manner as in Section5.1.2.193. In step 1, 6-methoxy- 1 -tetralone was used to make the1,3-diketone.

[0782] ESMS n/z333 (MH), C₂lH₂₀N₂0₂ =332 g/mol, HPLC purity =70%.

[0783] 5.1.2.198 Synthesis of3-(4-hydroxyphenyl)-2-[2-(trifluoromethyl)phenyl]-2,4,5-trihydrobenzo[g]1H-indazol-7-ol

[0784] This compound was synthesized in the same manner described inSection 5.1.2.149. In step 2, 2- trifluoromethylphenyl hydrazine wasused to form the pyrazole heterocycle.

[0785] ESMS m/z 423 (MH⁺), C₂₄H,,7F₃N₂0₂ =422 g/mol, HPLC purity =90%.5.1.2.199 Synthesis of4i4-ethyl-5phenyl-1-[2-(trifluoromethyl)phenyl]pyrazol-3-yl}phenol

[0786] This compound was synthesized based upon Scheme 1.

[0787] Step 1: Same as step 1 in Section 5.1.2.6.4-methoxy-butyrylphenone and benzoylchloride were used as startingmaterials.

[0788] Step 2: Same as step 2 in Section 5.1.2.6.2-trifluoromethylphenyl hydrazine was used to form the pyrazoleheterocycle. Step 3: Demethylation was performed as described in SchemeI to afford the final product.

[0789] ESMS m/z 409 (MH⁺), C₂₄Hl₉F₃N₂0 =408 g/mol, HPLC purity =99%5.1.2.200 Synthesis of4-[4-ethyl-3-(4-hydroxyphenyl)-5-methylpyrazolyl]phenol

[0790] This compound was synthesized based upon Scheme 1.

[0791] Step 1: Same as step I in Section 5.1.2.6.4-methoxy-butyrylphenone and acetylchloride were used as startingmaterials.

[0792] Step 2: Same as step 2 in Section 5.1.2.6. 4-methoxyphenylhydrazine was used to form the pyrazole heterocycle.

[0793] Step 3: Demethylation was performed asdescribed in Scheme I toafford the final product.

[0794] ESMS m/z 295 (MH“), C₁₈Hl₈N₂0₂ =294 g/mol, HPLC purity =99%.

[0795] 5.1.2.201 Synthesis of3-(4-hydroxyphenyl)-2-methyl-2-hydrobenzo[g]1H-indazol-6-ol

[0796] This compound was synthesized based upon Scheme 1.

[0797] Step 1: Same as step 1 in Section 5.1.2.149.5-methoxy-1-tetralone and p-anisoyl chloride were used as startingmaterials.

[0798] Step 2: Same as step 2 in Section 5.1.2.149. 4-methoxyphenylhydrazine was used to form the pyrazole heterocycle.

[0799] Step 3: Oxidation with 2,3-dichloro-5,6-dicyano- 1,4-benzoquinone(DDQ). To the above product in dry toluene was added DDQ (1.1 equiv.).The solution was refluxed overnight, quenched with sat. NaHCO₃, K₂CO₃and extracted with CH₂Cl₂. The combined organic layers were dried overMg₂SO₄ and evaporated in vacuo to give a solid residue. Purificationwith flash column chromatography yield product.

[0800] Step 4: Demethylation was performed as described for Step C inScheme 1 to afford the final product.

[0801] Step 5: The product was purified by HPLC using a C₁₈ column(Reliasil-BDXC18, 10×50 mm, Ranin Dynamax) running a first buffer ofH₂O/0.1% TFA and a second buffer of HCN/0.1% TFA through a gradient from5-95% of the second buffer over a nine-minute period at a flow rate often ml/min.

[0802] ESMS m/z 291 (MH⁺), C₁₈H₁₄N₂O₂=290 g/mol, HPLC purity=70%.

[0803] 5.1.2.202 Synthesis of3-(4-hydroxyphenyl)-2-methyl-2-hydrobenzo[g]1H-indazol-8-ol

[0804] This compound was synthesized in the same manner as described inSection 5.1.2.201. In step 1, 7-methoxy-1-tetralone and p-anisoylchloride were used as starting materials.

[0805] ESMS m/z 291 (MH⁺), C₁₈H₁₄N₂O₂=290 g/mol, HPLC purity=70%.

[0806] 5.1.2.203 Synthesis of3-(4-hydroxyphenyl)-2-[2-(trifuoromethyl)phenyl]-2-hydrobenzo[g]1H-indazol-7-ol

[0807] This compound was synthesized in the same manner as Section5.1.2.201. In step 1, 6-methoxy-1-tetralone and p-anisoyl chloride wereused as starting materials. In step 2, 2-trifluoromethylphenyl hydrazinewas used to form the pyrazole.

[0808] ESMS m/z 421 (MH⁺), C₂₄H₁₅F₃N₂O₂ =420 g/mol, HPLC purity=90%.

[0809] 5.1.2.204 Synthesis of2-cylobutyl-3-(4-hydroxyphenyl)-2-hydrobenzo[g]1 H-indazol-7-ol

[0810] This compound was synthesized based upon Scheme 4.

[0811] Steps 1, 2 and 3: Same as corresponding steps in Section5.1.2.197.

[0812] Step 4: Oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone(DDQ). Same as step 3 in Section 5.1.2.201.

[0813] Step 5: Demethylation was performed as described in Scheme 1 toafford the final product.

[0814] ESMS m/z 331 (MH), C₂₁H₁₈N₂O₂ =330 g/mol, HPLC purity=60%.

[0815] 5.1.2.205 Synthesis of4-{4-ethyl-3-(4-methoxyphenyl)-1-[2-(trifluoromethyl)phenyl]pyrazol-5yl}phenol

[0816] This compound is a derivative of the final product in Section5.1.2.53. To an acetone solution of 4-{4-ethyl-5-(4-hydroxyphenyl)-1-[2-(trifluoromethyl)phenyl]pyrazol-3-yl} phenol (1.0 equiv.) wasadded potassium carbonate (1.0 equiv.) and dimethylsulfate (1.0 equiv.).The mixture was stirred at rt overnight and routine work-up afforded amixture of starting material, mono-methylated product and di-methylatedproduct. HPLC using a C₁₈ column (Reliasil -BDXC18, 10×50 mm, RaninDynamax) running a first buffer of H₂O/0.1% TFA and a second buffer ofHCN/0.1% TFA through a gradient from 5-95% of the second buffer over anine-minute period at a flow rate of ten ml/min afforded the titlecompound as an off-white powder after lyophilization.

[0817] ESMS m/z 439 (MH⁺), C₂₅H₂₁F₃N₂O₂=438 g/mol, HPLC purity=98%.

[0818] 5.1.2.206 Synthesis of4-{4-ethyl-5(4-methoxyphenyl)-1-[2-(tifluoromethyl)phenyl]pyrazol-3-yl}phenol

[0819] This compound is the regioisomer of Section 5.1.2.205 andproduced as described therein.

[0820] ESMS m/z 439 (MH⁺), C₂₅H₂₁F₃N₂O₂ =438 g/mol, HPLC purity=98%.

[0821] 5.1.2.207 Synthesisof4-(5(4-acetyloxyphenyl)-4ethyl-1-1[2-(trifluoromethyl)phenyl]pyrazol-3-yl}phenylacetate

[0822] This compound is a derivative of the final product in Section5.1.2.53. To a THF solution of 4-{4-ethyl-5-(4-hydroxyphenyl)-1-[2-(trifluoromethyl)phenyl]pyrazol-3-yl}phenol was added acetylchloride (3.0 equiv.) and pyridine (3.0 equiv.). The mixture was stirredat rt for 24 h, poured into cold NaHCO₃, extracted with EtOAc. Theorganic extracts were washed with brine, dried with Na₂SO₄ andconcentrated in vacuo. Purification afforded the product as a whitepowder.

[0823] ESMS m/z 509 (MH⁺), C₂₈H₂₃F₃N₂O₄=508 g/mol, HPLC purity=98%.

[0824] 5.1.2.208 Synthesis of4-{4-ethyl-5-(4-hydroxyphenyl)-1-[2-(trifluoromethyl)phenyl}pyrazol-3-yl}phenylacetate

[0825] This compound is a derivative of the final product in Section5.1.2.53. To a THF solution of4-{4-ethyl-5-(4-hydroxyphenyl)-l-[2-(trifluoromethyl)phenyl]pyrazol-3-yl}phenolwas added acetyl chloride (1.0 equiv.) and pyridine (2.0 equiv.). Themixture was stirred at rt for 24 h, poured into cold NaHCO₃, extractedwith EtOAc. The organic extracts were washed with brine, dried withNa₂SO₄ and concentrated in vacuo to give a mixture of starting material,mono-acylated product and di-acylated product. HPLC isolation using aC₁₈ column (Reliasil-BDXCI8, 10×50 mm, Ranin Dynamax) running a firstbuffer of H₂O/0.1% TFA and a second buffer of HCN/0.1% TFA through agradient from 5-95% of the second buffer over a nine-minute period at aflow rate of ten ml/min. and purification followed by lyophilizationafforded the title product as a white powder.

[0826] ESMS m/z 467 (MH⁺), C₂₆H₂₁F₃N₂O₃=466 g/mol, HPLC purity=98%.

[0827] 5.1.2.209 Synthesis of4-{4-ethyl-3(4-hydroxyphenyl)-1-[2-(trifluoromethyl)phenyl]pyrazoI-5yl}phenylacetate

[0828] This compound is the regioisomer of Section 5.1.2.208. Thesynthesis and isolation procedures are the same as in that Section.

[0829] ESMS m/z 467 (MH⁺), C₂₆H₂lF₃N₂O₃ =466 g/mol, HPLC purity=98%.

[0830] 5.1.2.210 Synthesis of4-{5[4-(2,2dimethylpropanoyloxy)phenyl]-4-ethy-1-[2-(trifluoromethyl)phenyl]pyrazol-3-yl}phenyl2,2-dimethylpropanoate

[0831] This compound is a derivative of the final product in Section5.1.2.53. To a THF solution of4-{4-ethyl-5-(4-hydroxyphenyl)-1-[2-(trifluoromethyl)phenyl]pyrazol-3-yl}phenol was added pivaloyl chloride (3.0 equiv.) andpyridine (3.0 equiv.). The mixture was stirred at rt for 24 h, pouredinto cold NaHCO₃, extracted with EtOAc. The organic extracts were washedwith brine, dried with Na₂SO₄ and concentrated in vacuo. Purification byHPLC using a C₁₈ column (Reliasil-BDXC18, 10×50 mm, Ranin Dynamax)running a first buffer of H₂O/0.1% TFA and a second buffer of HCN/0.1%TFA through a gradient from 5-95% of the second buffer over anine-minute period at a flow rate of ten ml/min afforded the product asa white powder.

[0832] ESMS m/z 593 (MH⁺), C₃₄H₃₅F₃N₂O₄ =592 g/mol, HPLC purity=98%.

[0833] 5.1.2.211 Synthesis of4-{4-ethyl-5-(4-hydroxyphenyl)-1-[2-(trifluoromethyl)phenyl]pyrazol-3-yl}phenyl2,2dimethylpropanoate

[0834] This compound is a derivative of the final product in Section5.1.2.53. To a THF solution of 4-{4-ethyl-5-(4-hydroxyphenyl)-1[2-(trifluoromethyl)phenyl]pyrazol-3-yl}phenol was added pivaloylchloride (1.0 equiv.) and pyridine (2.0 equiv.). The mixture was stirredat rt for 24 h, poured into cold NaHCO₃, extracted with EtOAc. Theorganic extracts were washed with brine, dried with Na₂SO₄ andconcentrated in vacuo to give a mixture of starting material,mono-acylated product and di-acylated product. HPLC HPLC using a Clscolumn (Reliasil-BDXCI8, 10×50 mm, Ranin Dynamax) running a first bufferof H₂O/0.1 % TTA and a second buffer of HCN/0.1% TFA through a gradientfrom 5-95% of the second buffer over a nine-minute period at a flow rateof ten ml/min and purification followed by lyophilization afforded thetitle product as a white powder.

[0835] ESMS m/z 509 (MH⁺), C₂₉H₂₇F₃N₂O₃ =508 g/mol, HPLC purity=98%.

[0836] 5.1.2.212 Synthesis of4-{4-ethyl-3-(4-hydroxyphenyl)-1-12-(tflfluoromethyl)phenyl]pyrazol-5-yl}phenyl2,2-dimethylpropanoate

[0837] This compound is the regioisomer of Section 5.1.2.211. Thesynthesis and isolation procedures are the same as in that Section.

[0838] ESMS m/z 509 (MH⁺), C₂₉H₂₇F₃N₂O₃ =508 g/mol, HPLC purity=98%.

[0839] 5.1.2.213 Synthesis of 3-(4-hydroxyphenyl)-1-methylbenzo[g]1H-indazol-6-ol

[0840] This compound is the regioisomer of Section 5.1.2.201. Thesynthesis and isolation procedures are the same as in Section 5.1.2.201.

[0841] ESMS m/z 291 (MH⁺), C₁₈H,₁₄N₂O₂=290 g/mol, HPLC purity=99%.

[0842] 5.1.2.214 Synthesis of3-(4-hydroxyphenyl)-1-methylbenzo[g]1H-indazol-8-ol

[0843] This compound is the regioisomer of Section 5.1.2.202. Thesynthesis and isolation procedures are the same as in Section 5.1.2.202.

[0844] ESMS m/z 291 (MH⁺), C₁₈H₁₄N₂O₂ =290 g/mol, HPLC purity=97%.

[0845] 5.1.2.215 Synthesis of1-cyclobutyl-3-(4-hydroxyphenyl)benzo[g]1H-indazol-7o

[0846] This compound is the regioisomer of Section 5.1.2.204. Thesynthesis and isolation procedures are the same as in Section 5.1.2.204.

[0847] ESMS m/z 291 (MH⁺), C₁₈H₁₄N₂O₂ =290 g/mol, HPLC purity=97%.

[0848] 5.1.2.216 Synthesis of4-14-bromo-1cyclobutyl-5(4-hydroxyphenyl)pyrazol-3-yl]phenol

[0849] This compound was synthesized based upon Scheme 4.

[0850] Step 1: Formation of 1,3-diketones. Same as Step 1 in Section5.1.2.146.

[0851] Step 2 and 3: Same as corresponding steps in Section 5.1.2.167.

[0852] Step 4: Bromination. To a solution of the above pyrazole (1.0equiv.) in anhydrous CHCl₃ at reflux (70° C.) under argon was addeddropwise bromine (1.01 equiv.) in anhydrous CHCl₃ solution. The mixturewas stirred for 50 min at reflux, followed by addition of 10% Na₂S₂O₃ insaturated NaHCO₃ aqueous solution. The aqueous-organic solution wasseparated and the aqueous layer was extracted with CH₂Cl₂. The combinedorganic phases were dried over Na₂SO₄ and rotary evaporated to give ayellow solid that was washed with EtOAc to afford pale yellow solid as1-[4-bromo-1-cyclobutyl-3-(4-methoxyphenyl)pyrazol-5-yl]-4-methoxybenzene.

[0853] Step 5: Demethylation was performed as described in Scheme I toafford the final product.

[0854] ESMS: m/z 385 (MH⁺), C₁₉H₁₇BrN₂O₂ =385 g/mol; HPLC purity=91.6%.

[0855] 5.1.2.217 Synthesis of3,5-bis(4-hydroxypheny)-1-cyclobutylpyrazolA-yl 4-hydroxyphenyl ketone

[0856] This compound was synthesized based upon Scheme 4.

[0857] Step 1˜4: Same as corresponding steps in Section 5.1.2.216.

[0858] Step 5: Acylation. To a solution of the above 4-bormopyrazole(1.0 equiv.) in anhydrous THF at −98° C. under argon was added n-BuLi(1.2 equiv., 1.6 M in hexane). The resultant solution was stirred for 1h at −98° C. and then transferred dropwise to a solution of4-allyoxybenzoyl chloride (1.2 equiv.) in THF at −78° C. through adouble-tipped needle. The reaction mixture was stirred overnight at −78°C., diluted with water, and then acidified with 10% aqueous citric acid.The organic layer was dried over Na₂SO₄and purified with flashchromatography (CH₂Cl₂) to give acylated product.

[0859] Step 6: Demethylation was performed as described in Scheme 1 toafford the final product.

[0860] ESMS: m/z 427 (MH⁺), C₂₆H₂₂N₂O₄ =426 g/mol; HPLC purity=84.1%.

[0861] 5.1.2.218 Synthesis of3,5-bis(4-methoxyphenyl)-1-cyclobutylpyrazol-4-yl4-(2-piperidylethoxy)phenylketone

[0862] This compound was synthesized based upon Scheme 4 and Scheme 5.

[0863] Step 1˜5: Same as corresponding steps in Section 5.1.2.217.

[0864] Step 6: Selective removal of allyl protecting group. A mixture ofthe above pyrazole (1.0 equiv.), pyrrolidine (20 equiv.),triphenylphosphine (0.05 equiv.) and tetrakis(tiphenylphosphine)palladium(0) (0.05 equiv.) in THF was heated to reflux overnight. Thesolution was concentrated in vacuo and the crude material was purifiedby flash column chromatography (ethyl acetate/hexane 1:3).

[0865] Step 7: Alkylation. A mixture of the phenol (1.0 equiv., obtainedfrom step 6), 1-(2-chloroethyl)piperidine monohydrochloride (1.2 equiv.)cesium carbonate (2.5 equiv) in DMF (30ml) was heated at 100° C.overnight. The solids were removed by filtration, the filtrate wasconcentrated in vacuo and the residue was taken up into ethyl acetate.The solution was washed with water, brine, dried over sodium sulfate,filtered and concentrated in vacuo to give the title compound.

[0866] ESMS: m/z 566 (MH⁺), C₃₅H₃₉N₃O₄ =565 g/mol; HPLC purity=82.5%.

[0867] 5.1.2.219 Synthesis of3,5-bis(4-hydroxyphenyl)-1cyclobutylpyrazol-4-yl4-(2-piperidylethoxy)phenyl ketone

[0868] This compound was synthesized based upon Scheme 4 and Scheme 5.

[0869] Step 1˜7: Same as corresponding steps in Scheme 5.1.2.218.

[0870] Step 8: Demethylation was performed as described in Scheme 1 toafford the final product.

[0871] ESMS: m/z 538 (MH⁺), C₃₃H₃₅N₃O₄ =537 g/mol; HPLC purity=88.1%.

[0872] 5.1.2.220 Synthesis of4{4-ethyl-3-(4-hydroxyphenyl)-1-[2-(trifluoromethyl)phenyl]pyrazol-5yl-2-fluorophenol

[0873] This compound was synthesized in the same manner as Section5.1.2.53. In step 1, 4′-methoxybutyrylphenone and 53-fluoro-4-methoxybenzoyl chloride were used as starting materials.

[0874] ESMS: m/z 443 (MH⁺), C₂₄H₁₈F₄N₂O₂ =442 g/mol; HPLC purity=90%.

[0875] 5.1.2.221 Synthesis of4-{5-(4-butanoyoxypheny)-4-ethyl-1-[2-(trifluoromethyl)phenyl]pyrazol-3-yl}phenylbutanoate

[0876] This compound is a derivative of the final product in Section5.1.2.53. To a THF solution of4-{4-ethyl-5-(4-hydroxyphenyl)-1-[2-(trifluoromethyl)phenyl]pyrazol-3-yl}phenolwas added butyryl chloride (3.0 equiv.) and pyridine (3.0 equiv.). Themixture was stirred at rt for 24 h, poured into cold NaHCO₃, extractedwith EtOAc. The organic extracts were washed with brine, dried withNa2SO4 and concentrated in vacuo. Purification afforded the product as awhite powder.

[0877] ESMS: m/z 565 (MH⁺), C₃₂H₃₁F₃N₂O₄ =564 g/mol; HPLC purity=98%.

[0878] 5.1.2.222 Synthesis of4-[3-(4-butanoyloxyphenyl)-4-ethyl-1-methylpyrazol-5-yl]phenyl butanoate

[0879] This compound is a derivative of the final product in Section5.1.2.147. To a THF solution of 4-[4-ethyl-5-(4-hydroxyphenyl)- 1-methylpyrazol-3-yl]phenol was added butyryl chloride (3.0 equiv.) andpyridine (3.0 equiv.). The mixture was stirred at rt for 24 h, pouredinto cold NaHCO₃, extracted with EtOAc. The organic extracts were washedwith brine, dried with NaSO₄ and concentrated in vacua. Purificationafforded the product as a white powder.

[0880] ESMS: m/z 435 (MH⁺), C₂₆H₃₀N₂O₄ =434 gimol; HPLC purity=98%.

[0881] 5.1.2.223 Synthesis of4-[5-(4-acetyloxyphenyl)-4-ethyl-1-methylpyrazol-3-yl]phenyl acetate

[0882] This compound is a derivative of the final product in Section5.1.2.147. To a THF solution of 4-[4-ethyl-5-(4-hydroxyphenyl)-1-methylpyrazol-3-yl]phenol was added acetyl chloride (3.0 equiv.) andpyridine (3.0 equiv.). The mixture was stirred at rt for 24 h, pouredinto cold NaHCO₃, extracted with EtOAc. The organic extracts were washedwith brine, dried with NaSO₄ and concentrated in vacuo. Purificationafforded the product as a white powder.

[0883] ESMS: m/z 379 (MH⁺), C₂₂H₂₂N₂O₄ =378 g/mol; HPLC purity=98%.

[0884] 5.1.2.224 Synthesis of3,5-bis(4-hydroxyphenyl)-1-[2-(tnfluoromethy!)phenyl]pyrazol1-y44-(2-piperidylethoxy)phenyl ketone, chloride

[0885] This compound was synthesized in the same manner as Section5.1.2.219. In Step 2, 2-trifluoromethylphenyl hydrazine was used to formthe pyrazole heterocycle.

[0886]¹H NMR (d₆-DMSO): δ8.89 (s, 1H), 8.79(s, 1H), 7.14−5.73 (m, 15H),3.562 (broad t, 2H,), 2.64 (m, 4H), 2.15 (m, 2H), 0.89 (m, 6H); LC/MSm/z 628 (MH⁺), C₃₆H₃₂F₃N₃O₄ =627 g/mol; purity=99%.

[0887] 5.1.2.225 Synthesis of4-{5-[4-(4-butylcyclohexylcarbonyloxy)phenyf]-l-cyclobutA-4-ethylpyrazol-3-yl}phenyl4-butylcyclohexanecarboxylate

[0888] This compound is a derivative of product in Section 5.1.2.167.Pyrazole 4-[1-cyclobutyl-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenolwas dissolved in THF. To this solution was added EDC (1.5equiv.), DMAP(0.1equiv.), DIEA (1.5equiv.), and trans-4-n-butylcycloxehanoic acid(3equiv.) and the reaction was allowed to stir for 16 h at RT. Ethylacetate was then added and the reaction was washed with 10% citric acid,10% NaHCO₃, brine and dried (Na₂SO₄). After removing solvent theproducts (a mixture of bis-acylated and mono-acylated products) wereisolated by flash chromatography (5-30%EtOAc/DCM).

[0889]¹H NMR (CDCl₃):δ0.80−0.99 (13H, m), 1.13−1.28 (15H, m), 1.47−1.62(4H, m), 1.72−1.86 (5H, m), 2.05−2.19 (6H, m), 2.37−2.49 (4H, m),2.66−2.79 (2H, m), 4.41 (1H, pent., J=8.4 Hz), 7.06 (2H, d, J=8.8 Hz),7.12 (2H, d, J=8.7 Hz), 7.23 (2H, d, J=8.7 Hz), 7.64 (2H, d, J=8.7 Hz);ESMS: m/z 667 (MH⁺), C₄₃H₅₈N₂O₄=666 g/mol.

[0890] 5.1.2.226 Synthesis of4-[1-cyclobutyl-4-ethyl-5(4-hydroxyphenyl)pyrazol-3-yl]phenyl4-butylcyclohexanecarboxylate

[0891] This compound is a derivative of the product described in Section5.1.2.167. Synthetic procedure is same as Section 5.1.2.225. The mixtureof product was isolated and purified by HPLC using a Cls column(Reliasil-BDXC18, 10×50 mm, Ranin Dynamax) running a first buffer ofH₂O/0.1% TFA and a second buffer of HCN/0.1% TFA through a gradient from5-95% of the second buffer over a nine-minute period at a flow rate often ml/min.

[0892]¹H NMR (CDCl₃): δ0.84−1.03 (8H, m), 1.16-1.31 (8H, m), 1.48−1.66(4H, m), 1.74−1.89 (2H, m), 2.09−2.22 (4H, m), 2.40−2.51 (2H, m),2.69−2.80 (2H, m), 4.50 (1H, pent., J=8.2 Hz), 5.26 (1H, s), 6.85 (2H,d, J=8.7 Hz), 7.09 (2H, d, J=8.7 Hz), 7.11 (2H, d, J=8.6 Hz), 7.64 (2H,d, J=8.8 Hz); ESMS: m/z 501 (MH⁺), C₃₂H₄₀N₂O₃=500 g/mol; HPLCpurity=98.2%.

[0893] 5.1.2.227 Synthesis of4-[1cyclobutyl-4-ethyl-3-(4-hydroxyphenyl)pyrazol-5-yl]phenyl4-butylcydohexanecarboxylate

[0894] This compound is a derivative of product in Section 5.1.2.167.Synthetic procedure is same as Section 5.1.2.225. The mixture of productwas isolated and purified by HPLC.

[0895]¹H NMR (CDCl₃): δ0.85−1.04 (8H, m), 1.17−1.32 (8H, m), 1.49−1.66(4H, m), 1.74−1.91 (2H, m), 2.10×2.23 (4H, m), 2.40−2.54 (2H, m),2.72−2.84 (2H, m), 4.51 (1H, pent., J=8.2 Hz), 5.04 (1H, s), 6.84 (2H,d, J=8.8 Hz), 7.16 (2H, d, J=8.6 Hz), 7.27 (2H, d, J=8.7 Hz), 7.54 (2H,d, J=8.8 Hz); ESMS: m/z 501 (MH⁺), C₃₂H₄₀N₂O₃ =500 g/mol; HPLCpurity=98.8%.

[0896] 5.1.2.228 Synthesis of4-[1-cyclobutyl4-ethyl-5-(4-hydroxy-2-methylphenyl)pyrazol-3-yl]-3-methylphenol

[0897] This compound was synthesized based upon Scheme 5.

[0898] Synthetic procedure was same as for Section 5.1.2.167. In Step 1,4′-methoxy-2′-methylacetophenone and 4-methoxy-2-methylbenzoyl chloridewere used as starting materials.

[0899] ESMS: m/z 363 (MH⁺), C₂₃H₂₆N₂O₂=362 g/mol; HPLC purity=95%.

[0900] 5.1.2.229 Synthesis of4-[4-ethyl-5-(4-hydroxy-2-methylphenyl)-1-[2-(trifluoromethyl)phenyl]pyrazol-3-yl}3-methylphenol

[0901] This compound was synthesized based upon Scheme 1.

[0902] Synthetic procedure was same as for Section 5.1.2.53. In Step 1,4′-methoxy-2′-methylacetophenone and 4-methoxy-2-methylbenzoyl chloridewere used as starting materials.

[0903] ESMS: m/z 453 (MH⁺), C₂₆H₂₃ F₃N₂O₂ 452 g/mol; HPLC purity=95%.

[0904] 5.1.2.230 Synthesis of4-[1-cyclobutyl-5-(4-hydroxyphenyl)-4-propylpyrazol-3-yl]phenol

[0905] This compound was synthesized based upon Scheme 1.

[0906] Step 1-3: Same as corresponding steps in Section 5.1.2.216.

[0907] Step 4: Alkylation. To a solution of 4-bromopyrazole (I equiv.,obtained from step 3) in THF at −78° C. was added nBuLi (1.1 equiv., 1.6M in hexane). After the solution was stirred at −78° C. for 1.5 h, itwas added dropwise into a solution of the bromopropane (1.2 equiv.) inTHF at −78° C. After 15 min., the solution was allowed to warm to roomtemperature and stirred overnight. After quenching reaction with 1 MHCl, the layers were separated and the aqueous layer extracted withEtOAc (×3). The combined organic layers were washed with saturatedNaHCO₃ (×1) and brine, dried over Na₂SO₄, filtered and concentrated toafford a crude product mixture. Flash chromatography yielded thealkylated product.

[0908] Step 5: Demethylation was performed as described in Scheme 1 toafford the final product.

[0909]¹H NMR (CDCl₃/DMSO, 6:1): δ0.36(3H, t, J=7.2 Hz), 0.94−0.99 (2H,m), 1.27−1.34(1H, m), 1.40−1.45 (1H, m), 1.81−1.89 (2H, m), 2.03−2.07(2H, m), 2.35−2.47 (2H, m), 4.15−4.24 (1H, m), 6.52 (2H, d, J=8.8 Hz),6.57 (2H, d, J=8.6 Hz), 6.73 (2H, d, J=8.6 Hz), 7.14 (2H, d, J=8.8 Hz),8.55 (1H, s), 8.87 (1H, s); ESMS: n/z 349 (MH⁺), C₂₂H₂₄N₂O₂=348 g/mol;HPLC purity=84.9%.

[0910]4-[1-cyclobutyl-5-(4-hydroxyphenyl)-4-prop-2-enylpyrazol-3-yl]phenol

[0911] This compound was synthesized in the same manner as Section5.1.2.230. In step 4, allyl bromide was used for alkylation.

[0912]¹H NMR (CDCl3/DMSO, 6:1): δ1.78−1.91 (2H, m), 2.29−2.37 (2H, m),2.73−2.83 (2H, m), 3.26−3.28 (2H, m), 4.67−4.73 (1H, m), 4.91 (1H, dd,J=17.1 Hz, 1.9 Hz), 5.03 (1H, dd, J=10.1Hz, 1.9 Hz), 5.89−5.99 (1H, m),6.95 (2H, d, J=8.8 Hz), 7.01 (2H, d, J=8.7 Hz), 7.25 (2H, d, J=8.8 Hz),7.64 (2H, d, J=8.8 Hz); ESMS: m/z 347 (MH⁺), C₂₂H₂₂N₂O₂=346 g/mol; HPLCpurity =82.2%.

[0913] 5.1.2.231 Synthesis of4-[1-cyclobutyl-5(4-hydroxyphenyl)-4-methylpyrazol-3-yl]phenol

[0914] This compound was synthesized in the same manner as Section5.1.2.156. In step 3, chlorocyclobutane was used for alkylation.

[0915]¹H NMR (CDCl3/DMSO, 6:1): δ1.30−1.37 (1H, m), 1.44−1.51 (1H, m),1.70 (3H, s), 1.86−1.93 (2H, m), 2.40−2.46 (2H, m), 4.24−4.33 (1H,m),6.55 (2H, d, J=8.8 Hz), 6.60 (2H, d, J=8.6 Hz), 6.76 (2H, d, J=8.8Hz), 7.20 (2H, d, J=8.8 Hz), 8.55 (I H, s), 8.87 (1H, s); ESMS: m/z 321(MH⁺), C₂₀H₂₀N₂O₂=320 g/mol; HPLC purity=86.2%.

[0916] 5.1.2.232 Synthesis of 4-[1-cyclobutyl-3-(4-hydroxyphenyl)-4-phenylpyrazol-5-yI]phenol

[0917] This compound was synthesized in the same manner as Section5.1.2.231. In step 1, 1-(4-methoxyphenyl)-2-phenylethan-1-one was usedto make the 1,3-diketone.

[0918]¹H NMR (CDCl₃/DMSO, 6:1): δ1.44−1.49 (1H, m), 1.59−1.62 (1H, m),1.99−2.07 (2H, m), 2.58−2.64 (2H, m), 4.38−4.46 (1H, m), 6.48 (2H, d,J=8.8 Hz), 6.56 (2H, d, J=8.7 Hz), 6.72−6.77 (3H, m), 6.85−6.88 (2H, m),7.04 (2H, d, J=8.8 Hz), 8.47 (1H, s), 8.82 (1H, s); ESMS: m/z 383 (MH⁺),C₂₅H₂₂N₂O₂=382 g/mol; HPLC purity=94.8%

[0919] 5.1.2.233 Synthesis of4-[1-cylobutyl-5(4-hydroxyphenyl)-4-benzylpyrazol-3-yl]phenol

[0920] This compound was synthesized in the same manner as Section5.1.2.231. In step 1, 1-(4-methoxyphenyl) -3-phenylpropan- 1-one wasused to make the 1,3-diketone.

[0921]¹H NMR (CDCl₃/DMSO, 6:1): δ1.30−1.37 (1H, m), 1.45−1.51 (1H, m),1.87−1.94 (2H, m), 2.40−2.50 (2H, m), 3.46 (2H, s), 4.23−4.29 (1H, m),6.41 (2H, d, J=8.6 Hz), 6.49 (2H, d, J=8.6 Hz), 6.64 (4H, t, J=8.6 Hz),6.74 (1H, t, J=7.4 Hz), 6.80 (2H, t, J=7.6 Hz), 7.05 (2H, d, J=8.6 Hz),8.50 (1H, s), 8.84 (1H, s); ESMS: m/z 397 (MH+), C₂₆H₂₄N₂O₂=396 g/mol;HPLC purity=91.5%.

[0922] 5.1.2.234 Synthesis of4-[1-cyclobutyl-5-(4-hydroxyphenyl)-4-iodopyrazol-3-yl]phenol

[0923] This compound was synthesized in the same manner as Section5.1.2.216. In step 4, instead of bromination, iodonation was performed.

[0924]¹H NMR (CDCl₃/DMSO, 6:1): δ 1.26-1.33 (1H, m), 1.39-1.44 (1H, m),1.82-1.89 (2H, m), 2.30-2.40 (2H, m), 4.22-4.31 (1H, m), 6.50 (2H, d,J=8.6 Hz), 6.56 (2H, d, J=8.8 Hz), 6.76 (2H, d, J=8.8 Hz), 7.30 (2H, d,J=8.6 Hz); ESMS: m/z 433 (MH+), C₁₉H₁₇IN₂O₂=432 g/mol; HPLCpurity=81.3%.

[0925] 5.1.2.235 Synthesis of2-cyclobutyl-3-(4-hydroxyphenyl)-4,5,6-trihydrobenzo[c]pyrazolo[4,3a][annulen-8-ol

[0926] This compound was synthesized in the same manner as Section5.1.2.197. In step 1, 7-methoxy-1-benzosuberone was used to form the1,3-diketone.

[0927]¹H NMR (CDCl₃): δ 1.75-1.90 (3H, m), 2.16 (2H, pent, J=7.0 Hz),2.37-2.46 (3H, m), 2.54 (2H, t, J=7.0 Hz), 2.68-2.79 (2H, m), 4.97-5.04(1H, m), 6.83 (2H, dd, J=8.2, 2.5 Hz), 6.86 (1H, d, J=2.5 Hz), 6.91 (2H,d, J=8.6 Hz), 7.19 (1H, d, J=8.2 Hz), 7.50 (2H, d, J=8.7 Hz); ESMS: m/z347 (MH+), C₂₂H₂₂N₂O₂=346 g/mol; HPLC purity=97.0%.

[0928] 5.1.2.236 Synthesis of1-cyclobutyl-3-(4-hydroxyphenyl)-4,5,6-trihydrobenzo[c]pyrazolo[4,5-a][7]annulen-8-ol

[0929] This compound is the regioisomer of Section 5.1.2.235. HPLC usinga C₁₈ column (Reliasil-BDXC18, 10×50 mm, Ranin Dynamax) running a firstbuffer of H₂O/0.1% TFA and a second buffer of HCN/0.1% TFA through agradient from 5-95% of the second buffer over a nine-minute period at aflow rate of ten ml/minwas used for separation of the two regioisomers.

[0930]¹H NMR (CDCl₃): δ 1.70-1.86 (2H, m), 1.96-2.03 (2H, m), 2.26-2.34(2H, m), 2.49 (2H, t, J=7.0 Hz), 2.68-2.74 (4H, m), 4.71-4.79 (1H, m),6.71 (1H, d, J=2.5 Hz), 6.76 (1H, dd, J=8.4, 2.5 Hz), 6.96 (2H, d, J=8.6Hz), 7.20 (2H, d, J=8.8 Hz), 7.77 (1H, d, J=8.4 Hz); ESMS: m/z 347(MH+), C₂₂H₂₂N₂O₂=346 g/mol; HPLC purity=97.1%.

[0931] 5.1.2.237 Synthesis of2-[3,5-bis(4-hydroxyphenyl)-1cydobutylpyrazol-4-yl]phenol

[0932] This compound was synthesized based upon Scheme 4.

[0933] Step 1˜4: Same as corresponding steps in Section 5.1.2.216.

[0934] Step 5: Suzuki coupling of the above 4-bromopyrazole with arylboronic acid. Reaction was carried out under an atmosphere of nitrogenand solvents were degassed by bubbling nitrogen for 2 h prior to thereaction. Pd(PPh₃)₄ (0.04 eq) in DMF was added to the 4-bromopyrazole(obtained from step 4) and 2-methoxyphenylboronic acid (orvinyltributyltin) (1.1 eq). Sodium carbonate (0.4mL, 2M) was then added.The reaction was sealed and allowed to stand overnight at 90° C. Ethylacetate (2OmL) was then added and the reaction was washed with water andbrine. The organic fractions were filtered and concentrated underreduced pressure. Residues were lyophilised in 90%MeCN/R₂O. Purificationof the compound was achieved by teturation with 60% MeCN/H₂O and HPLCpurification.

[0935] Step 5: Demethylation was performed as described for Scheme 1.

[0936]¹H NMR (CDCl₃ & DMSO-d₆): δ 1.36-1.61 (2H, m), 1.95-2.06 (2H, m),2.50-2.60 (2H, m), 4.41 (1H, pent, J=7.8 Hz), 6.36 (2H, d, J=8.6 Hz),6.37 (1H, t, J=6.0 Hz), 6.45 (2H, d, J=8.8 Hz), 6.48 (1H, d, J=6.0 Hz),6.61 (1H, d, J=7.6 Hz), 6.71 (2H, d, J=8.6 Hz), 6.75 (I H, t, J=6.6 Hz),7.06 (2H, d, J=8.4 Hz), , 7.32 (1H, s), 8.45 (1H, s), 8.76 (1H, s); ESMSm/z 399 (MH+), C₂₅H₂₂N₂O₃=398 g/mol; HPLC purity=81.7%.

[0937] 5.1.2.238 Synthesis of4-[1-cyclobutyl-3-(4-hydroxyphenyl)4-(2-methylphenyl)pyrazol-5-yl]phenol

[0938] This compound was synthesized in the same manner as Section5.1.2.237. In step 5, 2-methylphenylboronic acid was used for coupling.

[0939]¹H NMR (CDCl₃ & DMSO-d₆): δ 1.25-1.58 (2H, m), 1.66 (3H, s),2.02-2.15 (2H, m), 2.61-2.76 (2H, m), 4.49 (1H, pent, J=7.8 Hz), 6.44(2H, d, J=8.0 Hz), 6.53 (2H, d, J=8.2 Hz), 6.68 (2H, d, J=8.0 Hz),6.80-6.92 (4H, m), 7.03 (2H, d, J=8.2 Hz), 8.39 (1H, s), 8.74 (1H, s);ESMS m/z 397 (MH+), C₂₆H₂₄N₂O₂=396 g/mol; HPLC purity=94.6%.

[0940] 5.1.2.239 Synthesis of4-{4-[3,5-bis(trifluoromethyl)phenyl]-1-cyclobutyl-3-(4-hydroxyphenyl)pyrazol-5-yl}phenol

[0941] This compound was synthesized in the same manner as Section5.1.2.237. In step 5, 3,5-di-trifluoromethylphenylboronic acid was usedfor coupling.

[0942]¹H NMR (CDCl₃ & DMSO-d₆): δ 1.51-1.76 (2H, m), 2.09-2.18 (2H, m),2.61-2.72 (2H, m), 4.52 (1H, pent, J=7.9 Hz), 6.61 (2H, d, J=8.6 Hz),6.71 (2H, d, J=8.2 Hz), 6.83 (2H, d, J=8.4 Hz), 7.07 (2H, d, J=8.4 Hz),7.24 (2H, s), 7.39 (1H, s); ESMS m/z 519 (MH+), C₂₇H₂₀F₆N₂O₂=518 g/mol;HPLC purity=84.7%.

[0943] 5.1.2.240 Synthesis of3-[3,5-bis(4-hydroxyphenyl)-cyclobutylpyrazol-4-yl]phenol

[0944] This compound was synthesized in the same manner as Section5.1.2.237. In step 5, 3-methoxyphenylboronic acid was used for coupling.

[0945]¹H NMR (CDCl₃ & DMSO-d₆): δ 1.24-1.47 (2H, m), 1.81-2.10 (2H, m),2.41 (2H, pent, J=9.7 Hz), 4.23 (1H, pent, J=8.3 Hz), 6.05 (1H, d, J=7.6Hz), 6.09 (1H, s), 6.17 (1H, d, J=8.2 Hz), 6.27 (2H, d, J=8.2 Hz), 6.37(2H, d, J=8.0 Hz), 6.52 (1H, d, J=7.8 Hz), 6.56 (2H, d, J=8.2 Hz), 6.87(2H, d, J=8.2 Hz); ESMS m/z 399 (MH⁺), C₂₅H₂₂N₂O₃=398 g/mol; HPLCpurity=89.3%.

[0946] 5.1.2.241 Synthesis of4-}1-cyclobutyl-3-(4-hydroxyphenyl)-4-[3-(trifluoromethyl)phenyl]pyrazol-5-yl}phenol

[0947] This compound was synthesized in the same manner as Section5.1.2.237. In step 5, 3 -trifluoromethylphenylboronic acid was used forcoupling.

[0948]¹H NMR (CDCl₃ & DMSO-d₆): δ 1.27-1.53 (2H, m), 1.86-1.97 (2H, m),2.47 (2H, pent, J=9.9 Hz), 4.39 (1H, pent, J=8.4 Hz), 6.47 (2H, d, J=7.8Hz), 6.55 (2H, d, J=7.8 Hz), 6.68 (2H, d, J=7.8 Hz), 6.82 (2H, d, J=8.2Hz), 6.96 (2H, d, J=7.6 Hz), 7.07 (2H, d, J=8.2 Hz); MS m/z 451 (MH+),C₂₆H₂₁F₃N₂O₂=450 g/mol; HPLC purity=99.4%.

[0949] 5.1.2.242 Synthesis of4-}1-cyclobutyl-3-(4-hydroxyphenyl)4-[4-(trifluoromethyl)phenyl]pyrazol-5-yl}phenol

[0950] This compound was synthesized in the same manner as Section5.1.2.237. In step 5, 4-trifluoromethylphenylboronic acid was used forcoupling.

[0951]¹H NMR (CDCl₃& DMSO-d₆): δ 1.39-1.61 (2H, m), 1.96-2.04 (2H, m),2.57 (2H, pent, J=9.9 Hz), 4.30 (1H, pent, J=8.3 Hz), 6.36 (2H, d, J=7.8Hz), 6.46 (2H, d, J=7.6 Hz), 6.60 (2H, d, J=7.8 Hz), 6.80-6.91 (5H, m),6.97 (1H, d, J=7.6 Hz); ESMS m/z 451 (MH+), C₂₆H₂₁F₃N₂O₂=450 g/mol; HPLCpurity=92.2%.

[0952] 5.1.2.243 Synthesis of4-[1-cyclobuyl-3-(4-hydroxyphenyl)-4-(2-thienyl)pyrazol-5-yl]phenol

[0953] This compound was synthesized in the same manner as Section5.1.2.237. In step 5, 2-thiophenylboronic acid was used for coupling.

[0954]¹H NMR (CDCl₃ & DMSO-d₆): δ 1.36-1.63 (2H, m), 1.94-2.03 (2H, m),2.55 (2H, pent, J=9.8 Hz), 4.36 (1H, pent, J=9.0 Hz), 6.38 (1H, d, J=3.5Hz), 6.48 (2H, d, J=8.2 Hz), 6.56 (1H, t, J=5.1 Hz), 6.57 (2H, d, J=8.2Hz), 6.78 (2H, d, J=8.2 Hz), 6.82 (1H, d, J=5.1 Hz), 7.09 (2H, d, J=8.4Hz); ESMS imlz 399 (MH⁺), C₂₃H₂₀N₂O₂S=388 g/mol; HPLC purity=99.1%.

[0955] 5.1.2.244 Synthesis of4-[1-cyclobutyl-3-(4-hydroxyphenyl)4-(3-thienyl)pyrazol-5-yl]phenol

[0956] This compound was synthesized in the same manner as Section5.1.2.237. In step 5, 3-thiophenylboronic acid was used for coupling.

[0957]¹H NMR (CDCl₃& DMSO-d₆): δ 1.30-1.56 (2H, m), 1.88-1.98 (2H, m),2.50 (2H, pent, J=9.9 Hz), 4.31 (1H, pent, J=8.3 Hz), 6.36 (1H, dd,J=4.9, 1.2 Hz), 6.43 (1H, dd, J=3.0, 1.2 Hz), 6.44 (2H, dd, J=8.8, 1.2Hz), 6.53 (2H, d, J=8.8 Hz), 6.70 (2H, d, J=8.4 Hz), 6.78 (1H, dd,J=4.9, 3.0 Hz), 7.00 (2H, dd, J=8.8, 1.2 Hz); ESMS m/z 399 (MH+),C₂₃H₂₀N₂O₂S=388 g/mol; HPLC purity=82.9%.

[0958] 5.1.2.245 Synthesis of4-[1-cyclobutyl-3-(4-hydroxyphenyl)4-vinylpyrazol-5-yl]phenol

[0959] This compound was synthesized in the same manner as Section5.1.2.237. In step 5, vinylboronic acid was used for coupling.

[0960]¹H NMR (CDCl₃ & DMSO-d): δ 1.64-1.89 (2H, m), 2.19-2.29 (2H, m),2.80 (2H, pent, J=9.8 Hz), 4.59 (1H, pent, J=8.4 Hz), 4.85 (1H, d,J=11.7 Hz), 4.99 (1H, d, J=17.7 Hz), 6.48 (1H, dd, J=18.0, 11.5 Hz),6.92 (2H, d, J=7.6 Hz), 6.98 (2H, d, J=7.6 Hz), 7.16 (2H, d, J=8.0 Hz),7.51 (2H, d, J=8.0 Hz), 8.90 (1H, s), 9.23 (1H, s); ESMS m/z 333 (MH+),C₂₁H₂₀N₂O₂=332 g/mol; HPLC purity=86.4%.

[0961] 5.2 Biological Activity of Compounds of the Invention

[0962] 5.2.1 In Vivo Assays

[0963] 5.2.1.1 Allen-Doisy Test for Estrogenicity

[0964] This test is used to evaluate a test compound for estrogenicactivity by observation of cornification of the vaginal epithelium of inovariectornized rats after administration of a test compound (Allen andDoisy 1923; Mühlbock 1940; Terenius 1971).

[0965] Mature female Hsd/Cpb rats, having initial weights between about150-200 g, were obtained from a commercial supplier (Harlan-CPB, Horst,The Netherlands). The rats were housed in housed in aluminium cages in alight- and temperature-controlled room (14 hours light/10 hours dark at19° C.-23° C.). Four rats were housed per cage. The rats were providedfree access to standard pelleted food and to tap water. After a periodof acclimatization (a few days) the rats were ovariectomized bilaterallyunder ether anaesthesia. Vaginal smears were taken over a period of 4-5days. Rats showing positive smears were discarded.

[0966] The rats of each treatment group were housed in two juxtaposedcages. Each experiment consisted of 2+n groups of eight rats per group.Two reference groups received the reference compound (estradiol, 1,3,5(10)-estratriene-3,17β-diol for subcutaneous (“sc”) administration;ethinylestradiol for oral administration); n groups received the testcompound. For subcutaneous administration, between 0.1 μg and 0.2 μgtotal dose/rat (approx. 0.4-0.8 μg/kg total dose) was used. For oraladministration, 0.008-0.016 mg total dose/rat (approx. 0.032-0.064 mg/kgtotal dose) was used. Vehicles used for sc administration were (inpreferential order): arachis oil, arachis oil with 100 ml/l benzylalcohol; gelatin (5.0 g/l) and mannitol (50 g/l) in water;methylcellulose (2.0 g/l) and NaCl, (9.0 g/l) in water; or any othersuitable vehicle. For oral administration, the vehicles used were (inpreferential order): gelatin (5.0 g/l) and mannitol (50 g/l) in water;methylcellulose (2.0 g/l) and NaCl, (9.0 g/l) in water; mulgofen (50g/l) (sold under the tradename ELF 719, GAF) and NaCl (9.0 g/l) inwater; or any other suitable vehicle.

[0967] Three weeks after ovariectomy, the rats were primed with a singlesc dose of I [g estradiol (in 0.1 ml arachis oil) to ensure maintenanceof sensitivity and greater uniformity of response. In the fourth week, 7days after priming, (preferably on a Monday), the reference or testcompound was administered in 3 equal doses, one in the afternoon of thefirst day of treatment, and two (one in the morning and one in theafternoon) of the second day of treatment. Compound doses were chosenbased on extrapolations of in vitro data obtained in theCHO-transactivation (Section) and/or binding assays for estrogenreceptor using known estrogen agonists and antagonists. For scadministration, the reference compound (estradiol) was administered intotal doses of 0.1-0.2 □g/rat. Test compounds were usually administeredin total doses of 0.01-1.0 mg/rat. Each total sc dose was dividedequally over three administrations, each in a dose volume of 0.25 ml.For oral administration, the reference compound (ethinylestradiol) wasadministered in total doses of 0.008-0.016 mg/rat. Test compounds areusually administered in total doses of 0.01-1.0 mg/rat. Each total oraldose was divided equally over 3 administrations, each in a dose volumeof 0.25 ml. For expression of doses per kg, an average body weight of250 g was assumed. Vaginal smears were taken in the afternoon of thethird day, in the morning and afternoon of the fourth day, and in themorning of the fifth day of the treatment week. Additional vaginalsmears were taken on succeeding days (in the morning) until theestrogenic response was complete. The vaginal smears were made onmicroscope slides. The slides were dried and fixed with 96% ethanol, andstained for about twenty minutes with Giemsa solution (Merck, Darmstadt,Germany), that had been diluted 1:10 with tap water, washed thoroughlyunder tap water, then dried. The percentage of cornified and nucleatedepithelial cells was estimated for each smear was evaluated undermicroscope observation (60×). The rats were allowed to rest for one week(week five of the experiment). The experiment was then repeated, withpriming on the sixth week and administration and observation during theseventh week, as described. The rats were then euthanized under deepanesthesia or with CO₂/O₂ gas.

[0968] The developmental phase of the vaginal epithelium for each ratwas evaluated using a scale from “a”-“g” determined as follows (Table1). The vaginal sequence of normal non-ovariectomized rats with a 4-dayestrous cycle is: diestrus→diestrus→proestrus→estrus. The usual phasesobserved in the mornings of the 4-day estrous cycle using the scale inTable 1 are therefore a, a, e, and g, respectively. The phases b, c, dand f are intermediates. TABLE 1 Percentage Of Percentage of NucleatedPercentage of Cornified Developmental Leucocytes Epithelial CellsEpithelial Cells Phase >67% — — a. diestrus 5-50% >50% — b. latediestrus <5% >50% — e. proestrus <5% — >50% f. estrus <5% <5% >90% g.estrus 5-33% — >50% d. metestrus 33-67% — <50% c. late metestrus

[0969] The number of rats with a positive response is a measure for theestrogenic activity of the test compound. The interpretation of theresults was made as shown in Table 2. TABLE 2 Percentage of Rats Showinga Positive Response Conclusion 0% inactive 1%-50% weakly active >50%active

[0970] 5.2.1.2 Anti-Allen-Doisy Test for Anti-Estrogenicity

[0971] This test is used to evaluate a test compound for anti-estrogenicactivity when administered in the presence of estrogen (Allen and Doisy1923; Jongh and Laqueur 1938; Mühlbock 1940; Emmens, Cox et al. 1959).More specifically, the ability of the test compound to counteract theestrogenic cornification of vaginal epithelium is determined.

[0972] Mature female Cpb rats, having initial weights between about150-200 g, were obtained from a commercial supplier (CPB-TNO, Zeist, TheNetherlands). The rats were housed in housed in aluminium cages in alight- and temperature-controlled room (14 hours light/10 hours dark at21° C.-23° C.). Four rats were housed per cage. The rats were providedfree access to standard pelleted food and to tap water. After a periodof acclimatization (a few days) the rats were ovariectomized bilaterallyunder ether anaesthesia. Vaginal smears were taken over a period of 4-5days. Rats showing positive smears were discarded.

[0973] The rats of each treatment group were housed in two juxtaposedcages. Each experiment consisted of 1+n groups of eight rats per group.One reference group received the reference compound (nafoxidine HCl); ngroups received the test compound. For oral administration, 0.25mg/rat/day (approx. 1.44 mg/kg/day) was used. Vehicles used forsubcutaneous (“sc”) administration were (in preferential order): arachisoil, arachis oil with 10% benzyl alcohol; gelatin (0.5%) and mannitol(5%) in water; and methylcellulose (0.2%) and NaCl (9.0 %) in water. Fororal administration, the vehicles used were (in preferential order):gelatin (0.5%) and mannitol (5%) in water; methylcellulose (0.2%) andNaCl (9.0 %) in water; and mulgofen (5%) (sold under the tradename ELF719, GAF) and NaCl (0.9%) in water.

[0974] Two weeks after ovariectomy, the rats were primed with a singlesc dose of 0.2 μg estradiol (in 0.1 ml arachis oil) administered dailyfor ten days to ensure maintenance of sensitivity and greater uniformityof response. Administration of estradiol was followed immediately byadministration of test compound or vehicle. Test compounds wereadministered at 1.0 mg/rat. For sc administration, the dose volume was0.1 ml; for oral administration, the dose volume was 0.25 ml. Vaginalsmears were taken daily throughout the administration period. Thevaginal smears were made on microscope slides. The slides were dried andfixed with 96% ethanol, and stained for about twenty minutes with Giemsasolution (Merck, Darmstadt, Germany), that had been diluted 1:10 withtap water, washed thoroughly under tap water, then dried. The percentageof conified and nucleated epithelial cells was estimated for each smearwas evaluated under microscope observation (60×). Following theexperiment, rats were euthanized under deep anesthesia or with CO₂/O₂gas.

[0975] The developmental phase of the vaginal epithelium for each ratwas evaluated using a scale from “a”-“g” determined as follows (Table3). The vaginal sequence of normal non-ovariectomized rats with a 4-dayestrous cycle is: diestrus→diestrus→proestrus→estrus. The usual phasesobserved in the mornings of the 4-day estrous cycle using the scale inTable 3 are therefore a, a, e, and g, respectively. The phases b, c, dand f are intermediates. TABLE 3 Percentage Of Percentage of NucleatedPercentage of Cornified Developmental Leucocytes Epithelial CellsEpithelial Cells Phase >67% — — a. diestrus 5-50% >50% — b. latediestrus <5% >50% — e. proestrus <5% — >50% f. estrus <5% <5% >90% g.estrus 5-33% — >50% d. metestrus 33-67% — <50% c. late metestrus

[0976] Smears showing any of phases e, f, or g were considered to beestrogenic (i.e., the vaginal epithelium showed cornification). Thefinal result was expressed as a ratio of the number of smears showingestrogenic response to the total number of smears collected from thethird day through the final day of the study. The number of rats with apositive response is a measure for the anti-estrogenic activity of thetest compound. The interpretation of the results was made as shown inTable 4. TABLE 4 Percentage of Rats Showing a Positive ResponseConclusion >70% inactive 35%-70% weakly active <35% active

[0977] 5.2.1.3 Immature Rat Uterotrophic Bioassay for Estrogenicity andAnti-Estrogenicity

[0978] Antiestrogenic activity is determined by the ability of a testcompound to suppress the increase in uterine wet weight resulting fromthe administration of 0.2 μg 17-β-estradiol (“E₂”) per day. Anystatistically significant decreases in uterine weight in a particulardose group as compared with the E₂ control group are indicative ofanti-estrogenicity.

[0979] One hundred forty (140) female pups (I19 days old) in the 35-50 gbody weight range are selected for the study. On day 19 of age, when thepups weigh approximately 35-50 g, they are body weight-order randomizedinto treatment groups. Observations for mortality, morbidity,availability of food and water, general appearance and signs of toxicityare made twice daily. Pups not used in the study are euthanized alongwith the foster dams. Initial body weights are taken just prior to thestart of treatment at day 19 of age. The final body weights are taken atnecropsy on day 22 of age.

[0980] Treatment commences on day 19 of age and continues until day 20and 21 of age. Each animal is given three subcutaneous (“sc”) injectionsdaily for 3 consecutive days. Three rats in each of the control and mid-to high-level dose test groups are anesthetized with a ketamine/xylazinemixture. Their blood is collected by exsanguination using a 22 gaugeneedle and 5 ml syringe flushed with 10 USP units sodium heparin/mlthrough the descending vena cava; and then transferred into a 5 ml greentop plasma tube (sodium heparin (freeze-dried), 72 USP units). Plasmasamples are collected by centrifugation, frozen at −70° C., and analyzedusing mass spectrographic to determine the presence and amount of testcompound in the serum. Blood chemistry is also analyzed to determineother blood parameters. The uteri from the rats are excised and weighed.The remaining rats are sacrificed by asphyxiation under CO₂. The uterifrom these rats are excised, nicked, blotted to remove fluid, andweighed to the nearest 0.1 mg.

[0981] In order to determine whether the test compound significantlyaffected final body weight, a parametric one-way analysis of variance(ANOVA) is performed (SIGMASTAT version 2.0, available commercially fromJandel Scientific, San Rafael, Calif.). Estrogen agonist and antagonistactivity is assessed by comparing uterine wet weights across treatmentgroups using a parametric ANOVA on loglo transformed data. The data aretransformed to meet assumptions of normality and homogeneity of varianceof the parametric ANOVA. The F value is determined and aStudent-Newman-Kuels multiple range test is performed to determine thepresence of significant differences among the treatment groups. The testcompound is determined to act as a mixed estrogen agonist/antagonist ifthe test compound does not completely inhibit the17β-estradiol-stimulated uterotrophic response.

[0982] 5.2.1.4 Estrogen Receptor Antagonist Efficacy In MCF-7 XenograftModel

[0983] MCF-7 human mammary tumors from existing in vivo passages areimplanted subcutaneously into 95 female Ncr-nu mice. A 17-β-estradiolpellet (Innovative Research of America) is implanted on the sideopposite the tumor. Both implants are performed on the same day.

[0984] Treatment is started when the tumor sizes are between 75 mg and200 mg. Tumor weight is calculated according to the formula for thevolume of an ellipsoid, $\frac{l \times w^{2}}{2}$

[0985] where I and w are the larger- and smaller dimensions of the tumorand unit tumor density is assumed. The test compounds are administeredBID: q7h×2, with one drug preparation per week. The test compounds arestored at +4° C. between injections. The dose of test compound isdetermined according to the individual animal's body weight on each dayof treatment. Gross body weights are determined twice weekly, startingthe first day of treatment. Mortality checks are performed daily. Micehaving tumors larger than 4,000 mg, mice having ulcerated tumors, as andmoribund mice are sacrificed prior to the day of study termination Thestudy duration is limited to 60 days from the day of tumor implantationbut termination could occur earlier as determined to be necessary.Terminal bleeding of all surviving mice is performed on the last day ofthe experiment. Statistical analysis is performed on the data gathered,including mortality, gross individual and group average body weights ateach weighing, individual tumor weights and median group tumor weight ateach measurement, the incidence of partial and complete regressions andtumor-free survivors, and the calculated delay in the growth of themedian tumor for each group.

[0986] 5.2.1.5 OVX Rat Model

[0987] This model evaluates the ability of a compound to reverse thedecrease in bone density and increase in cholesterol levels resultingfrom ovariectomy (Black, Author et aL 1994; Willson, Author et al.1997). Three-month old female rats are ovariectomized (“ovx”), and testcompounds are administered daily by subcutaneous route beginning one daypost-surgery. Sham operated animals and ovx animals with vehicle controladministered are used as control groups. After 28 days of treatment, therats are weighed, the overall body weight gains obtained and the animalseuthanized. Blood bone markers (e.g., osteocalcin and bone-specificalkaline phosphatase), total cholesterol, and urine markers (e.g.,deoxypyridinoline and creatinine) are measured. Uterine wet weights arealso obtained. Both tibiae and femurs are removed from the test animalsfor peripheral quantitative computed tomography scanning or othermeasurement of bone mineral density. Data from the ovx and test vehicleanimals are compared to the sham and ovx control animals to determinetissue specific estrogenic/antiestrogenic effects of the test compounds.

[0988] 5.2.2 In vitro Assays

[0989] 5.2.2.1 ERα Binding Assays

[0990] ERα receptor (0.2 mg/ml, Affinity Bioreagents) was diluted toabout 2×10⁻³ mg/ml in phosphate-buffered saline (“PBS“) at a pH of 7.4.Fifty microliters l of the ERα-PBS solution was then added to each thewells of a flashplate (Wallac SCINTISCTRIPS). The plates were sealed andstored in the dark at 4° C. for 16-18 hours. The buffered receptorsolution is removed just prior to use, and the plates were washed 3times with 200 microliters per well of PBS. The washing was typicallyperformed using a slow dispense of reagent into the wells to avoidstripping the receptor from the well surface.

[0991] For library screening, 150 microliters of 1 nM ³H-estradiol (NewEngland Nuclear, Boston, Mass.) in 20 mM Tris-HCl, 1 mM EDTA, 10%glycerol, 6 mM monothioglycerol, 5 mM KCl, pH 7.8 was mixed with 50microliters of the test compound (in same buffer) in a 96 wellmictrotiter plate (Costar 3794), resulting in a final estradiolconcentration of 0.6 nM. In addition, several dilutions of estradiol,centered on the IC₅₀ of 1-2 nM were also added to individual wells togenerate a standard curve. The plates were gently shaken to mix thereagents. A total of 150 microliters from each of the wells is added tothe corresponding wells of the pre-coated ERx plates. The plates weresealed (Packard #6005185) and the components in the wells were incubatedeither at room temperature for 4 hours or at 4° C. overnight. Thereceptor bound ligand was read directly after incubation using ascintillation counter (TR₁ LUX, Wallac). The amount of receptor boundligand was determined directly, i.e, without separation of bound fromfree ligand. If estimates of both bound and free ligand were required,the supernatant was removed from the wells, liquid scintillant added,and the wells counted separately in a liquid scintillation counter.

[0992] 5.2.2.2 ERβ Binding Assays

[0993] ERβ receptor (˜0.2 mg/ml, Affinity Bioreagents) was diluted toabout 2×10⁻³ mg/ml in phosphate-buffered saline (“PBS”) at a pH of 7.4.Fifty microliters of the ERβ-PBS solution was then added to each thewells of a flashplate (Wallac SCINTISCTRIPS). The plates were sealed andstored in the dark at 4° C. for 16-18 hours. The buffered receptorsolution is removed just prior to use, and the plates were washed 3times with 200 microliters per well of PBS. The washing was typicallyperformed using a slow dispense of reagent into the wells to avoidstripping the receptor from the well surface.

[0994] For library screening, 150 microliters of 1 nM ³H-estradiol (NewEngland Nuclear, Boston, Mass.) in 20 mM Tris-HCl, 1 mM EDTA, 10%glycerol, 6 mM monothioglycerol, 5 mM KCl, pH 7.8 was mixed with 50microliters of the test compound (in same buffer) in a 96 wellmictrotiter plate (Costar 3794), resulting in a final estradiolconcentration of 0.6 nM. In addition, several dilutions of estradiol,centered on the IC₅₀ of 1-2 nM were also added to individual wells togenerate a standard curve. The plates were gently shaken to mix thereagents. A total of 150 microliters from each of the wells is added tothe corresponding wells of the pre-coated ERβ plates. The plates weresealed (Packard #6005185) and the components in the wells were incubatedat room temperature either for 4 hours or at 4° C. overnight. Thereceptor bound ligand was read directly after incubation using ascintillation counter (TRILUX, Wallac). The amount of receptor boundligand was determined directly, ie., without separation of bound fromfree ligand. If estimates of both bound and free ligand were required,the supernatant was removed from the wells, liquid scintillant added,and the wells counted separately in a liquid scintillation counter.

[0995] 5.2.2.3 ERα/ERβ Transactivation Assays

[0996] 5.2.2.3.1 Construction of Transfected CHO Cells

[0997] The above-mentioned transfected CHO cells were derived from CHOKI cells obtained from the American Type Culture Collection (“ATCC”,Rockville, Md.). The transfected cells were modified to contain thefollowing four plasmid vectors: (1) pKCRE with DNA for the humanestrogen receptor, (2) pAG-60-neo with DNA for the protein leading toneomycin resistance, (3) pRO-LUC with DNA for the rat oxytocin promoterand for firefly luciferase protein, and (4) pDR₂ with DNA for theprotein leading to hygromycine resistance. All transformations withthese genetically modified CHO cells were performed under rec-VMTcontainment according to the guidelines of the COGEM (CommissieGenetische Modificatie). Screening was performed either in the absenceof estradiol (estrogenicity) or in the presence of estradiol(anti-estrogenicity).

[0998] Reagents

[0999] The following reagents were prepared using ultra pure water(milli-Q quality):

[1000] 1. Culture Medium

[1001] Dulbecco's MEM/HAM F12 powder (12.5 g/l; Gibco, Paisley, UK) wasdissolved in water. Sodium bicarbonate (2.5 grams/liter (“g/l”)),L-glutamine (0.36 g/l) and sodium pyruvate (5.5×10⁻² g/l) were added.This medium was supplemented with an aqueous mixture (0.50 ml/l medium)of ethanolamine (2.44 ml/l), sodium selenite (0.9 mg/l), and2-mercaptoethanol (4.2 ml/l). The pH of the medium was adjusted to7.0±0.1 with NaOH or HCl (1 mol/l), and the medium was sterilized bymembrane filtration using a filter having 0.2 μm pores. The resultingserum-free culture medium was stored at 4° C.

[1002] 2. Antibiotics Solution

[1003] Streptomycin sulfate (25 g; Mycofarm, Delft, The Netherlands) andsodium penicillin G (25 g; Mycofarm) were dissolved in 1 l water andsterilized by membrane filtration using a filter having 0.2 μm pores.

[1004] 3. Defined Bovine Calf Serum Supplemented (“DBCSS”)

[1005] DBCSS (Hyclone, Utah), sterilized by the manufacturer, wasinactivated by heating for 30 min at 56° C. with mixing every 5 min.Aliquots of 50 ml and 100 ml were stored at −20° C.

[1006] 4. Charcoal-Treated DBCSS (“cDBCSS”) Charcoal (0.5 g; Norit A)was washed with 20 ml water (3 times) and then suspended in 200 ml Trisbuffer. For coating 0.05 g dextran (T70; Phannacia, Sweden) is dissolvedin a suspension that was stirred continuously for 3 hours atroom-temperature. The resulting dextran-coated charcoal suspension wascentrifuged for 10 min at 8,000 N/kg. The supernatant was removed and100 ml DBCSS was added to the residue. The suspension was stirred for 30min at 45° C. under aseptic conditions. Following stirring, the charcoalwas removed by centrifugation for 10 μm at 8000 N/kg. The supernatantwas sterilized by membrane filtration using a first filter having a poresize of 0.8 pm followed by filtration with a second filter having a poresize of 0.2 Urn. The sterilized, heat-inactivated cDBCSS was stored at−20 C.

[1007] 5. Tris Buffer

[1008] Tromethamine (“Tris”, 1.21 g; 10 mmol) was dissolved inapproximately 950 ml water. The solution pH was adjusted to 7.4 usingHCl (0.2 mol/l) and the volume raised to 1 l with additional water. Thisbuffer was prepared fresh prior to use.

[1009] 6. Luclite Substrate Solution

[1010] Luclite luminescense kit, developed for firefly luciferaseactivity measurements in microtiter plates was obtained from acommercial source (Packard, Meriden, Conn.). Ten milliliters of theabove-described buffer solution was added to each flask of substrate.

[1011] Preparation of Transfected Cells

[1012] Under aseptic conditions, the above-described culture medium wassupplemented with antibiotics solution (2.5 ml/l) and heat-inactivatedcDBCSS (50 ml/l) to give complete medium. One vial of theabove-described recombinant CHO cells was taken from the seed stock inliquid nitrogen and allowed to thaw in water at approximately 37° C. ARoux flask (80 cc) was inoculated with about 5×10⁵ viable cells/ml incomplete medium. The flask was flushed with 5 % CO₂ in air until a pH of7.2-7.4 resulted. The cells were subsequently incubated at 37° C. Duringthis period, the complete medium was refreshed twice.

[1013] Following incubation the cell culture was trypsinized andinoculated at 1:10 dilution in a new flask (180 cc cell culturing) andat 5×10³ cells with 100 μl complete medium per well in a 96—well whiteculture plate for transactivation assays. The 96 well plates wereincubated over two days. The cells were grown as a monolayer at thebottoms of the wells and reached confluence after two days. After a cellculture period of 20 passages, new cells were taken from the seed stockin liquid nitrogen.

[1014] 5.2.2.3.2 Assay of Compounds

[1015] Assay for Estrogenicit

[1016] Experiments were performed in groups of three blocks, each blockin a separate microtiter plate. Each block included the following fourgroups Group Contents 1 One transactivation group of four wells, eachcontaining ethanol and transfected cells. This group was used toestimate total transactivation. 2 One total transactivation group offour wells containing beta-estradiol (1 × 10⁻⁷ M) and transfected cells.This group was used to estimate total transactivation of cells. 3 Threestandard groups of five wells each, containing five differentconcentrations of non-transfected and transfected cells. 4 Test orreference compound groups (n groups, n ≦ 21) of three wells each,containing three different concentrations of test or reference compoundand transfected cells.

[1017] Aliquots of ten pl of control, standard, test, and referencecompounds were added by pipette into wells of the relevant groups asdefined above. Each of the wells included 190 lu¹ of complete medium.Group Contents 1 Ethanol 2 Standard solution in ethanol (10⁻⁹ M, to beraised to 10⁻⁶ M final concentration). 3 Standard solutions in ethanol(0.47 × 10⁻¹¹ M, 0.95 × 10⁻¹¹ M, 1.95 × 10⁻¹¹ M, 3.9 × 10⁻¹¹ M, and 7.8× 10⁻¹¹ M, to be raised to 0.47 × 10⁻⁸ M, 0.95 × 10⁻⁸ M, 1.95 × 10⁻⁸ M,3.9 × 10⁻⁸ M, and 7.8 × 10⁻⁸ M respectively). 4 Test or referencecompound in six different concentrations 1 × 10⁻⁵ M, 3.16 × 10⁻⁶ M, 1 ×10⁻⁶ M, 3.16 × 10⁻⁷ M, 1 × 10⁻⁷ M, 3.16 × 10⁻⁸ M, respectively.

[1018] Assay for Anti-Estrogenicity

[1019] Experiments were performed in groups of three blocks, each blockin a separate microtiter plate. Each block included the following fourgroups, each group containing estradiol, 1, 3, 5 (10)-estratriene-3,17-β-diol (10⁻¹⁰M) in the final reaction mixture. Group Contents 1 Onetransactivation group of four wells, each containing ethanol andtransfected cells. This group was used to estimate totaltransactivation. 2 One group of completely inhibited transactivationgroup of four wells containing ICI 164,384 (10⁻⁶ M) and transfectedcells. This group was used to estimate complete inhibition oftransactivation. 3 Three standard groups of five wells each, containingfive different concentrations of non-transfected and transfected cells.4 Test or reference compound groups (n groups, n ≦ 21) of three wellseach, containing three different concentrations of test or referencecompound and transfected cells.

[1020] Aliquots of ten μl of control, standard, test, and referencecompounds were added by pipette into wells of the relevant groups asdefined above. Each of the wells included 190 μl of complete medium.Group Contents 1 Ethanol 2 Standard solution in ethanol (10⁻⁹ M, to beraised to 10⁻⁶ M final concentration). 3 Standard solutions in ethanol(0.47 × 10⁻¹¹ M, 0.95 × 10⁻¹¹ M, 1.95 × 10⁻¹¹ M, 3.9 × 10⁻¹¹ M, and 7.8× 10⁻¹¹ M, to be raised to 0.47 × 10⁻⁸ M, 0.95 × 10⁻⁸ M, 1.95 × 10⁻⁸ M,3.9 × 10⁻⁸ M, and 7.8 × 10⁻⁸ M respectively). 4 Test or referencecompound in six different concentrations 1 × 10⁻⁵ M, 3.16 × 10⁻⁶ M, 1 ×10⁻⁶ M, 3.16 × 10⁻⁷ M, 1 × 10⁻⁷ M, 3.16 × 10⁻⁸ M, respectively.

[1021] The microtiter plates were shaken for at least 15 minutes toensure dissolution of all compounds. Simultaneously, 100 μl estradiol,1, 3, 5 (10)-estratriene-3, 17-μ-diol (10⁻⁷ M) was added to 40 ml ofcomplete medium, shaken, and equilibrated to 37° C. About 100 μl of thissolution was added to microtiter white culture plates seeded theprevious day with 10⁴ transfected cells in 100 μl of complete medium.The microtiter white culture plates were gently shaken for at least 15minutes and incubated for 16 h at 37° C. in the dark under a humidifiedatmosphere flushed with 5 % CO₂ in air.

[1022] Finally, 200 μl of complete medium was removed from themicrotiter culture plates, while 50 μl of LUCLITE substrate solution wasadded to the remaining 50 μl of medium and cells. After ten minutescell, cell lysis was substantially complete. After sealing the top ofthe plate, luciferase activity was measured with a luminescence counter.Each sample was counted once for 2.5 s using a scintillation(luminescence) counter. All luminescence measurements were recorded on ateleprinter.

[1023] 5.2.2.3.3 Evaluation of Responses

[1024] The counting figures are corrected to a standardized plate andconverted into numbers of light flashes per second (“cps”). For eachblock (microtiter plate), the mean cps values for the total andnon-specific transactivation groups were calculated. For eachconcentration of standard (separate for each well), test and referencecompound, the percentage of transactivation activity relative to themaximum specific estradiol, 1, 3, 5 (10)-estratriene-3, 17-β-dioltransactivation activity was calculated using the formula:$\frac{\begin{matrix}{{{cps}\quad \left( {{standard}\text{/}{test}\quad {compound}} \right)} -} \\{{mean}\quad {cps}\quad \left( {\text{non-specific}\quad {transactivation}} \right.}\end{matrix}}{\begin{matrix}{{{cps}\quad \left( {{total}\quad {transactivation}} \right)} -} \\{{mean}\quad {cps}\quad \left( {\text{non-specific}\quad {transactication}} \right)}\end{matrix}} \times 100.$

[1025] The percentage in the three blocks was evaluated statisticallyusing the analysis of a 3-point parallel line assay in blocks. In orderto meet better the requirements for this analysis, the percentages werereplaced by their logit values. The log concentration-response curvesfor the standard, test, and reference compounds were tested forlinearity; and the latter curves also for parallelism with the curve forthe standard compound. If no significant curvature and no significantdeviation from parallelism at the 0.01 levels were found; then therelative transactivation activity of the test compound with respect toestradiol, 1, 3, 5 (10)-estratriene-3, 17-β-diol (potency ratio),together with the 95% confidence interval, was calculated. Forantagonist assays, the relative inhibitory potency of transactivationactivity of the test compound with respect to the standard antagonist,ICI 164,384 was calculated. For compounds showing significant agonist orantagonist activity in these initial screens, more accurate EC₅₀ valueswere determined by generating twelve-point curves with 3-fold dilutionsof the compounds. In this case, the range of concentrations was selectedbased on the compound activity in the initial screens.

[1026] The following compounds of the invention were determined to beactive (ie., have agonist or antagonist values of EC₅₀ ≦4×10⁻⁶ M (ERα)and/or EC₅₀≦4×10⁻⁶ M (ERβ)) against either or both ERα and ERβ:4-[5-(diphenylmethyl) -4-ethyl-1-methylpyrazol-3-yl]phenol,4-[4-ethyl-1-methyl-5-(2-phenylethyl)pyrazol-3-yl]phenol,4-(4-ethyl-1-methyl-5-(2-thienyl)pyrazol-3-yl)phenol,4-[1-methyl-5-(2-phenylethyl)-4-prop-2-enylpyrazol-3-yl]phenol,4-[1-methyl-5-(phenoxymethyl)-4-prop-2-enylpyrazol-3-yl]phenol,4-[3,5-bis(4-hydroxyphenyl)-1-methylpyrazol4-yl]phenol,4-[3,5-bis(4-hydroxyphenyl)-1-phenylpyrazol-4-yl]phenol,4-[1-(4-bromophenyl)-5-(4-hydroxyphenyl)-4-benzylpyrazol-3-yl]phenol,4-fl-(4-chloro-2-methylphenyl)-5-(4-hydroxyphenyl)4-benzylpyrazol-3-yl]phenol,4-[1-(2-chlorophenyl)-5-(4-hydroxyphenyl)-4-benylpyrazol-3-yl]phenol,4-[1-(3-chlorophenyl)-5-(4-hydroxyphenyl)4-benzylpyrazol-3-yl]phenol,4-[1-(4-chlorophenyl)-5-(4-hydroxyphenyl)-4-benzylpyrazol-3-yl]phenol,4-[3,4-bis(4-hydroxyphenyl)-1-(2-methylphenyl)pyrazol-5-yl]phenol,4-[3,4-bis(4-hydroxyphenyl)-1-(3 -fluorophenyl) pyrazol-5-yl]phenol,4-[3 ,4-bis(4-hydroxyphenyl)-1-(2-ethylphenyl)pyrazol-5-yl]phenol,4-[3,5-bis(4-hydroxyphenyl)-1-(4-fluorophenyl)pyrazol-4-yl]phenol,4-[1-(2,4-difluorophenyl)-3,4-bis (4-hydroxyphenyl)pyrazol-5-yl]phenol,4-{3,4-bis(4-hydroxyphenyl)-1-[2-(trifluoromethyl)phenyl]pyrazol-5-yl}phenol,4-[3 ,4-bis(4-hydroxyphenyl)-1-(2-fluorophenyl)pyrazol-5-yl]phenol,4-[3,4-bis(4-hydroxyphenyl)-1-(3-methylphenyl) pyrazol-5-yl]phenol,4-[3,4-bis(4-hydroxyphenyl)-1-(4-chloro-2-methylphenyl)pyrazol-5-yl]phenol,4-[3,5-bis(4-hydroxyphenyl)-1-(4-methylphenyl)pyrazol-4-yl]phenol,4-[1-(2,3-dichlorophenyl)-3,4-bis(4-hydroxyphenyl) pyrazol-5-yl]phenol,4-[3,4-bis(4-hydroxyphenyl)-1-(5-fluoro-2-methylphenyl)pyrazol-5-yl]phenol,4-[3 ,4-bis(4-hydroxyphenyl)-1-(2-chlorophenyl)pyrazol-5-yl]phenol,4-{3,4-bis(4-hydroxyphenyl)-1-[4-(tert-butyl)phenyl]pyrazol-5-yl}phenol,4-[3,4-bis(4-hydroxyphenyl)-1-(3-chlorophenyl)pyrazol-5-yl]phenol,4-[1-(2,4-dichlorophenyl)-3,4-bis (4-hydroxyphenyl)pyrazol-5-yl]phenol,4-[3,5-bis(4-hydroxyphenyl)-1-(4-chlorophenyl) pyrazol-4-yl]phenol,4-[1-(2,6-dichlorophenyl)-3,4-bis(4-hydroxyphenyl)pyrazol-5-yl]phenol,4-[3,4-bis (4-hydroxyphenyl)-1-(2,3-dimethylphenyl)pyrazol-5-yl]phenol,4-[3,4-bis(4-hydroxyphenyl)-1-(3-chloro-4-fluorophenyl)pyrazol-5-yl]phenol,4-{3,4-bis(4-hydroxyphenyl)-1-[4-(trifluoromethoxy)phenyl]pyrazol-5-yl}phenol,4-{3,4-bis(4-hydroxyphenyl)-1-[4-(trifluoromethyl)phenyl]pyrazol-5-yl}phenol,4-[3,5-bis(4-hydroxyphenyl)-1-(4-iodophenyl) pyrazol-4-yl]phenol, 4-{3,4-bis(4-hydroxyphenyl}1-[2-chloro-5-(trifluoromethyl)phenyl]pyrazol-5-yl}phenol, 4-[3,4-bis(4-hydroxyphenyl)-1-(1,3-dimethyl-5-nitropyrazol-4-yl) pyrazol-5-yl]phenol,4-{3,4-bis(4-hydroxyphenyl)-1-[5-chloro-3-(trifluoromethyl)(2-pyridyl)]pyrazol-5-yl}phenol,4-[3,4-bis(4-hydroxyphenyl)-1-(1,4-dimethylpyrazolo[4,5-e]pyridin-6-yl)pyrazol-5-yl]phenol,4-[3,5-bis(4-hydroxyphenyl)-1-(6-methylpyridazin-3-yl)pyrazol-4-yl]phenol,4-[3,4-bis(4-hydroxyphenyl)-1-(6-chloro-2-fluorophenyl)pyrazol-5-yl]phenol,4-[1-(2-fluorophenyl)-5-(4-methylphenyl)-4-benzylpyrazol-3-yl]phenol, 3-{[3,5-bis (4-hydroxyphenyl)-4-benzylpyrazolyl]methyl}phenol,1-[3,5-bis(4-hydroxyphenyl)-4-benzylpyrazolyl]-4-(methylsulfonyl)benzene,4-[5-(4-hydroxyphenyl)-1-(2,3,4,5,6-pentafluorophenyl)-4-benzylpyrazol-3-yl]phenol,4-{5-(4-hydroxyphenyl)-4-benzyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl}phenol, 4-[3,5-bis(4-hydroxyphenyl)-1-(2-pyridyl)pyrazol-4-yl]phenol,4-[1-(2,4-dimethylphenyl)-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4-[4-ethyl-5-(4-hydroxyphenyl)-1-(3-methylphenyl) pyrazol-3-yl]phenol,4-{4-ethyl-5-(4-hydroxyphenyl)-1-[4-(methylethyl)phenyl]pyrazol-3-yl}phenol,4-[4-ethyl-1-(3-fluorophenyl)-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4-[4-ethyl-1-(2-ethylphenyl)-5-(4-hydroxyphenyl) pyrazol-3-yl]phenol,4-[4-ethyl-1-(4-fluorophenyl)-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol, 4-[1-(2,4-difluorophenyl)-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4-{4-ethyl-5-(4-hydroxyphenyl)-1-[2-(trifluoromethyl)phenyl]pyrazol-3-yl}phenol,4-[4-ethyl-1-(2-fluorophenyl)-5-(4-hydroxyphenyl) pyrazol-3-yl]phenol,4-[4-ethyl-5-(4-hydroxyphenyl)-1-(2-methylphenyl)pyrazol-3-yl]phenol,4-[1-(3,5-dichlorophenyl)-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4-[1-(4-chloro-2-methylphenyl)-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4-[4-ethyl-5-(4-hydroxyphenyl)1-(4-methylphenyl)pyrazol-3-yl]phenol,4-[1-(2,3-dichlorophenyl)4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4-[1-(3,4-dimethylphenyl)4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4-[4-ethyl-1-(5-fluoro-2-methylphenyl)-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4-[1 -(2-chlorophenyl)-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4- {-[4-(tert-butyl)phenyl]-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl}phenol,4-[1-(3-chlorophenyl)4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4-[1-(2,4-dichlorophenyl)4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4-[1-(3,4-dichlorophenyl)-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4-[1-(4-chlorophenyl)4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4-[1-(2,6-dichlorophenyl)-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4-[1-(2,3-dimethylphenyl)-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4-[1-(3-chloro-4-fluorophenyl)4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol, 4-{4-ethyl-5-(4-hydroxyphenyl)-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl}phenol,4-{4-ethyl-5-(4-hydroxyphenyl)1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl}phenol,4-[4-ethyl-5-(4-hydroxyphenyl)-1-(4-iodophenyl) pyrazol-3-yl}phenol,4-[1-[2-chloro-5-(trifluoromethyl)phenyl]4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl}phenol,4-[1-(3,5-dichloro(4-pyridyl))-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4-{4-ethyl-5-(4-hydroxyphenyl)-1-[6-methyl-4-(trifluoromethyl)(2-pyridyl)]pyrazol-3-yl}phenol,4-[4-ethyl-5-(4-hydroxyphenyl)-1-quinoxalin-2-ylpyrazol-3-yl]phenol,4-{1-[3,5-bis(trifluoromethyl)phenyl]-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl}phenol,4-[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]benzenesulfonamide,4-[1-(1,3 -dimethyl-5-nitropyrazol-4-yl)-4-ethyl-3-(4-hydroxyphenyl)pyrazol-5-yl]phenol, -4-{1-[5-chloro-3-(trifluoromethyl)(2-pyridyl)]-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl}phenol,4-1-[3-chloro-5-(trifluoromethyl)(2-pyridyl)]-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl}phenol,4-[4-ethyl-5-(4-hydroxyphenyl)-1-(1,3,4-trimethylpyrazolo[4,5-e]pyridin-6-yl)pyrazol-3-yl]phenol,4-[1-(6-chloro-2-fluorophenyl)-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4-[4-ethyl-5-(4-hydroxyphenyl)-1-(2-pyridyl)pyrazol-3-yl]phenol,4-[4-ethyl-1-(3-hexadecylthiophenyl)-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4-[3,5-bis(4-hydroxyphenyl)-1-(3-hexadecylthiophenyl)pyrazol-4-yl]phenol,4-{4-ethyl-5-(4-hydroxyphenyl)-1-[(4-hydroxyphenyl)methyl]pyrazol-3-yl}phenol,4-(4-ethyl-5-(4-hydroxyphenyl)-1-{[4-(2-piperidylethoxy)phenyl]methyl}pyrazol-3-yl)phenol,4-{1-[(3-chlorophenyl)methyl]-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl}phenol,4-{4-ethyl-1-[(4-fluorophenyl)methyl]-5-(4-hydroxyphenyl)pyrazol-3-yl}phenol,4-{4-ethyl-5-(4-hydroxyphenyl)-1-[(3-methylphenyl)methyl]pyrazol-3-yl}phenol,4-{4-ethyl-5-(4-hydroxyphenyl)-1-[(4-nitrophenyl)methyl]pyrazol-3-yl}phenol,4-{4-ethyl-5-(4-hydroxyphenyl)-1-[(3-phenoxyphenyl)methyl]pyrazol-3-yl}phenol,2-[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]-1-(4-methylphenyl)ethan-1-one,2-[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]-1-(4-fluorophenyl)ethan-1-one,1-(3,4-dichlorophenyl)-2-[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]ethan-1-one,2-[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]-1-(2-hydroxyphenyl)ethan-1-one,4-[4-ethyl-5-(4-hydroxyphenyl)-1-benzylpyrazol-3-yl]phenol, 2-[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]-1-(4-bromophenyl)ethan-1-one,4-(1-{[4-(tert-butyl)phenyl]methyl}-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl)phenol,4-{2-[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]acetyl}benzenecarbonitrile,2-[3,5-bis(4-hydroxyphenyl)4-ethylpyrazolyl]-1-(4-phenylphenyl)ethan-1-one,2-[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]-1-(3-hydroxyphenyl)ethan-1-one,4-[1-(2,4-dimethylphenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol,4-[5-(4-hydroxyphenyl)1-(3-methylphenyl)-4-phenylpyrazol-3-yl]phenol,4-{5-(4-hydroxyphenyl)-1-[4-(methylethyl)phenyl]-4-phenylpyrazol-3-yl}phenol,4-[1-(3-fluorophenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol,4-[1-(2-ethylphenyl)-5-(4-hydroxyphenyl)4-phenylpyrazol-3-yl]phenol,4-[l-(4-fluorophenyl)3-(4-hydroxyphenyl)4-phenylpyrazol-5-yl]phenol,4-[1-(2,4-difluorophenyl)-5-(4-hydroxyphenyl)4-phenylpyrazol-3-yl]phenol,4-{5-(4-hydroxyphenyl)-4-phenyl-1-[2-(trifluoromethyl)phenyl]pyrazol-3-yl}phenol,4-[1-(2-fluorophenyl)-5-(4-hydroxyphenyl)4-phenylpyrazol-3-yl]phenol,4-[5-(4-hydroxyphenyl)-1-(2-methylphenyl)-4-phenylpyrazol-3-yl]phenol,4-[1-(3,5-dichlorophenyl)-5-(4-hydroxyphenyl)4-phenylpyrazol-3-yl]phenol,4-[1-(4-chloro-2-methylphenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol,4-[3-(4-hydroxyphenyl)-1-(4-methylphenyl)4-phenylpyrazol-5-yl]phenol,4-[1-(2,3-dichlorophenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol,4-[1-(3,4-dimethylphenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol,4-[1-(5-fluoro-2-methylphenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol,4-[1-(2-chlorophenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol,4-[1-(3-chlorophenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol,4-[1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol,4-[1-(3,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol,4-[1-(4-chlorophenyl)-3-(4-hydroxyphenyl)-4-phenylpyrazol-5-yl]phenol,4-[1-(2,6-dichlorophenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol,4-[1-(2,3-dirnethylphenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol,4-[1-(3-chloro-4-fluorophenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol,4-{5-(4-hydroxyphenyl)-4-phenyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl}phenol,4-{5-(4-hydroxyphenyl}4-phenyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl}phenol,4-[3-(4-hydroxyphenyl)-1-(4-iodophenyl)-4-phenylpyrazol-5-yl]phenol,4-{1-[2-chloro-5-(trifluoromethyl)phenyl]-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl}phenol,4-[1-(3,5-dichloro(4-pyridyl))-5-(4-hydroxypheny)-4-phenylpyrazol-3-yl]phenol,4-{5-(4-hydroxyphenyl)-1-[6-methyl-4-(trifluoromethyl)(2-pyridyl)]4-phenylpyrazol-3-yl}phenol,4-[5-(4-hydroxyphenyl)-4-phenyl-1-quinoxalin-2-ylpyrazol-3-yl]phenol, 4-{1-[3,5-bis(trifluoromethyl)phenyl]-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl}phenol,4-{1-[1,3-dimethyl-5-(nitromethyl)pyrazol-4-yl]-5-(4-hydroxyphenyl)4-phenylpyrazol-3-yl}phenol,4-{1-[5-chloro-3-(trifluoromethyl)(2-pyridyl)]-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl}phenol,4-{1-[3-chloro-5-(trifluoromethyl)(2-pyridyl)]-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl}phenol,4-[5-(4-hydroxyphenyl)-4-phenyl-1-(1,3,4-trimethylpyrazolo[4,5-e]pyridin-6-yl)pyrazol-3-yl]phenol,4-[3-(4-hydroxyphenyl)-1-(6-methylpyridazin-3-yl)-4-phenylpyrazol-5-yl]phenol,4-[1-(6-chloro-2-fluorophenyl)-5-(4-hydroxyphenyl)-4-phenylpyrazol-3-yl]phenol,4-[1,3-bis(4-hydroxyphenyl)-4-ethylpyrazol-5-yl]phenol,4-[1,3-bis(4-hydroxyphenyl)4-phenylpyrazol-5-yl]phenol,4-[1,3,5-tris(4-hydroxyphenyl)pyrazol-4-yl]phenol,4-[1,3-bis(4-hydroxyphenyl)pyrazol-5-yl]phenol,4-[4-ethyl-5-(4-hydroxyphenyl)-1-methylpyrazol-3-yl]phenol,4-[4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,3-(4-hydroxyphenyl)-2,4,5-trihydrobenzo [g]1H-indazol-7-ol,3-(4-hydroxyphenyl)-2-methyl-2,4,5-trihydrobenzo[g]1H-indazol-7-ol,3-(4-hydroxyphenyl)-2-phenyl-2,4,5-trihydrobenzo[g]1H-indazol-7-ol,1-[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]-4-(methylsulfonyl)benzene, 3-{[3,5-bis(4-hydroxyphenyl)pyrazolyl]methyl}phenol,1-[3,5-bis(4-hydroxyphenyl)-4-methylpyrazolyl]-4-(methylsulfonyl)benzene, 1-[3,5-bis(4-hydroxyphenyl)pyrazolyl]4-(methylsulfonyl)benzene, 3-{[3,5-bis(4-hydroxyphenyl)-4-methylpyrazolyl]methyl}phenol,3-{[3,5-bis(4-hydroxyphenyl)4-ethylpyrazolyl]methyl}phenol,8-[3,5-bis(4-hydroxyphenyl)4-ethylpyrazolyl]-N-butyl-N-methyloctanamide,3-(4-hydroxyphenyl)-2-methylindeno[3,2-c]pyrazol-6-ol,1-[1-cyclobutyl-4-ethyl-5-(4-methoxyphenyl)pyrazol-3-yl]-4-methoxybenzene,4-[1,4-diethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4-[4-ethyl-5-(4-hydroxyphenyl)-1-propylpyrazol-3-yl]phenol,4-[1-butyl4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4-[4-ethyl-5-(4-hydroxyphenyl)-1-(2-methylpropyl)pyrazol-3-yl]phenol,4-[4-ethyl-5-(4-hydroxyphenyl)-1-prop-2-enylpyrazol-3-yl]phenol,4-[1-(cyclohexylmethyl)-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4-[1-cyclobutyl4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4-[1-cyclohexyl-4-ethyl-5-(4-bydroxyphenyl) pyrazol-3-yl]phenol,4-[4-ethyl-5-(4-hydroxyphenyl)-1-(2-morpholin4-ylethyl)pyrazol-3-yl]phenol,2-[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]acetamide,1-[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]acetone,4-[1-cyclopentyl-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4-[4-ethyl-5-(4-hydroxyphenyl)-1-(methylethyl) pyrazol-3-yl]phenol, 4-[1-cycloheptyl-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,4-[1-(cyclopropylmethyl)-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,3-(4-hydroxyphenyl)-1-methylindeno [2,3-d]pyrazol-6-ol,4-[4-ethyl-5-(4-hydroxyphenyl)-1-phenylpyrazol-3-yl]phenol,4-[5-(4-hydroxyphenyl)-1,4-diphenylpyrazol-3-yl]phenol,2-{4-ethyl-5-(4-hydroxyphenyl)-1-[2-(trifluoromethyl)phenyl]pyrazol-3-yl}phenol, 3-{4-ethyl-5-(4-hydroxyphenyl)1-[2-(trifluoromethyl) phenyl]pyrazol-3-yl}phenol,3-1-(4-hydroxyphenyl)-3-(3-hydroxyphenyl)-4-methylpyrazo 1-5-yl]phenol,3-[3-(3-hydroxyphenyl)-4-methyl-1-phenylpyrazol-5-yl]phenol,3,5-bis(4-hydroxyphenyl)-4-ethyl-1-(methylsulfonyl) pyrazole,1-{[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]sulfonyl}-2-chlorobenzene,3,5-bis(4-hydroxyphenyl)-4-ethyl-1-[(4-methylphenyl)sulfonyl]pyrazole,3-(4-hydroxyphenyl)-2-methyl-2,4,5-trihydrobenzo[g]I H-indazol-6-ol,3-(4-hydroxyphenyl)-2-methyl-2,4,5-trihydrobenzo[g]1H-indazol-8-ol,3-(4-hydroxyphenyl)-2-[2-(trifluoromethyl)phenyl]-2,4,5-trihydrobenzo[g]1H-indazol-8-ol, 4-{3-(4-hydroxyphenyl)-1-[2-(trifluoromethyl) phenyl]pyrazol-5-yl}phenol,3-(4-hydroxyphenyl)-2,4,5-trihydrobenzo[g]1H-indazol-6-ol,4-]1-cyclopropyl-4-ethyl-5-(4-hydroxyphenyl) pyrazol-3-yl]phenol,4-(1-{[3,5-bis(4-hydroxyphenyl)-4-ethylpyrazolyl]methyl}4-ethyl-3-(4-hydroxyphenyl)pyrazol-5-yl)phenol,2-cyclobutyl-3-(4-hydroxyphenyl)-2,4,5-trihydrobenzo [g]1H-indazol-6-ol,4-[1-cyclobutyl-4-ethyl-5-(4-methoxyphenyl)pyrazol-3-yl]phenol,4-[5-(4-acetyloxyphenyl)-1-cyclobutyl-4-ethylpyrazol-3-yl]phenylacetate,4-[5-(4-butanoyloxyphenyl)-1-cyclobutyl-4-ethylpyrazol-3-yl]phenylbutanoate,2-cyclobutyl-3-(4-hydroxyphenyl)-2,4,5-trihydrobenzo[g]1H-indazol-7-ol,3-(4-hydroxyphenyl)-2-[2-(trifluoromethyl)phenyl]-2,4,5-trihydrobenzo[g]1H-indazol-7-ol,4-{4-ethyl-5-phenyl-1-[2-(trifluoromethyl) phenyl]pyrazol-3-yl}phenol,4-[4-ethyl-3-(4-hydroxyphenyl)-5-methylpyrazolyl]phenol,3-(4-hydroxyphenyl)-2-methyl-2-hydrobenzo [g]1H-indazol-6-ol,3-(4-hydroxyphenyl)-2-methyl-2-hydrobenzo[g]1H-indazol-8-ol,3-(4-hydroxyphenyl)-2-[2-(trifluoromethyl)phenyl]-2-hydrobenzo[g]H-indazol-7-ol,2-cyclobutyl-3-(4-hydroxyphenyl)-2-hydrobenzo[g]1H-indazol-7-ol,4-{4-ethyl-3-(4-methoxyphenyl)-1-[2-(trifluoromethyl)phenyljpyrazol-5-yl }phenol, 4-{4-ethyl-5-(4-methoxyphenyl)-1-[2-(trifluoromethyl) phenyl]pyrazol-3-yl} phenol, 4-{5-(4-acetyloxyphenyl)-4-ethyl-1-[2-(trifluoromethyl)phenyl]pyrazol-3-yl} phenyl acetate,4-{4-ethyl-5-(4-hydroxyphenyl)-1-[2-(trifluoromethyl)phenyl]pyrazol-3-yl} phenyl acetate,4-{4-ethyl-3-(4-hydroxyphenyl)-1-[2-(trifluoromethyl)phenyl]pyrazol-5-yl} phenyl acetate, 4-{5-[4-(2,2-dimethylpropanoyloxy)phenyl]-4-ethyl-l-[2-(trifluoromethyl)phenyl]pyrazol-3-yl} phenyl2,2-dimethylpropanoate, 4- {4-ethyl-5-(4-hydroxyphenyl)-1-[2-(trifluoromethyl)phenyl]pyrazol-3-yl} phenyl2,2-dimethylpropanoate, 4- {4-ethyl-3-(4-hydroxyphenyl)-1-[2-(trifluoromethyl)phenyl]pyrazol-5-yl} phenyl2,2-dimethylpropanoate, 3-(4-hydroxyphenyl)- 1-methylbenzoyl[g]1H-indazol-6-ol, 3-(4-hydroxyphenyl)- 1 -methylbenzo[g] 1H-indazol-8-ol,1 -cyclobutyl-3-(4-hydroxyphenyl) benzo[g] 1H-indazol-7-ol, 4-[4-bromo-1-cyclobutyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol,3,5-bis(4-hydroxyphenyl)- 1-cyclobutylpyrazol-4-yl 4-hydroxyphenylketone, 3,5-bis(4-methoxyphenyl)-1-cyclobutylpyrazol 4-yl4-(2-piperidylethoxy)phenyl ketone, 3,5-bis(4-hydroxyphenyl)-1-cyclobutylpyrazol4-yl 4-(2-piperidylethoxy)phenyl ketone, 4-{4-ethyl-3-(4-hydroxyphenyl)-1-[2-(trifluoromethyl)phenyl]pyrazol-5-yl}-2-fluorophenol,4-{5-(4-butanoyloxyphenyl)-4-ethyl-1-[2-(trifluoromethyl)phenyl]pyrazol-3-yl}phenylbutanoate, 4-[3-(4-butanoyloxyphenyl)-4-ethyl-1-methylpyrazol-5-yl]phenyl butanoate,4-[5-(4-acetyloxyphenyl)-4-ethyl-1-methylpyrazol-3-yl]phenyl acetate,3,5-bis(4-hydroxyphenyl)-1-[2-(trifluoromethyl)phenyl]pyrazol-4-yl4-(2-piperidylethoxy)phenyl ketone, chloride, 4-{5-[4-(4-butylcyclohexylcarbonyloxy)phenyl]-1-cyclobutyl-4-ethylpyrazol-3-yl}phenyl 4-butylcyclohexanecarboxylate,4-[1-cyclobutyl-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenyl4-butylcyclohexanecarboxylate, 4-[1-cyclobutyl-4-ethyl-3-(4-hydroxyphenyl)pyrazol-5-yl]phenyl4-butylcyclohexanecarboxylate, 4-[1-cyclobutyl-4-ethyl-5-(4-hydroxy-2-methylphenyl)pyrazol-3-yl]-3-methylphenol,4- {4-ethyl-5-(4-hydroxy-2-methylphenyl)-1-[2-(trifluoromethyl)phenyl]pyrazol-3-yl)-3-methylphenol,4-[1-cyclobutyl-5-(4-hydroxyphenyl)-4-propylpyrazol-3-yl]phenol,4-[1-cyclobutyl-5-(4-hydroxyphenyl)-4-prop-2-enylpyrazol-3-yl]phenol,4-[1-cyclobutyl-5-(4-hydroxyphenyl)-4-methylpyrazol-3-yl]phenol, 4-[1-cyclobutyl-3-(4-hydroxyphenyl)-4-phenylpyrazol-5-yl]phenol, 4-[1-cyclobutyl-5-(4-hydroxyphenyl)-4-benzylpyrazol-3-yl]phenol,4-[1-cyclobutyl-5-(4-hydroxyphenyl)4-iodopyrazol-3-yl]phenol,2-cyclobutyl-3-(4-hydroxyphenyl)-4,5,6-trihydrobenzo[c]pyrazolo[4,3-a][7]annulen-8-ol,and 1-cyclobutyl-3-(4-hydroxyphenyl)4,5,6-trihydrobenzo[c]pyrazolo[4,5-a][7]annulen-8-ol..

[1027] 5.2.2.4 MCF-7 Cell Proliferation Assays

[1028] This assay determines the estrogen agonist/antagonist activity ofa test compound by the effect of the test compound on the proliferationof MCF-7 cells as measured by the incorporation of5-bromo-2′-deoxyuridine (“BrdU”) in a chemiluminescent assay format.

[1029] MCF-7 cells (ATCC HTB-22) were maintained in log-phase cultureusing DMEM/HamF12 medium (v/v 1/1) that had been supplemented with 10%fetal bovine serum (“FBS”), at 37° C., and under at 5% CO₂ atmosphere.The cells were plated in a 96-well plate at a density of 7,000 cells perwell. After 24 hours, the cells were further incubated in phenolred-free DMEM/HamF12 medium supplemented with 10% FBS that had beenfiltered with dextran-coated charcoal to deplete endogenous estrogen(DCC-FBS). The cells were incubated in this medium for an additional 24hours, at which time either test compound at varying concentrations todetermine the IC₅₀ for the compound. Each test compound was incubatedwith the cells either in the absence of estradiol (detection of estrogenagonist activity) or in the presence of 1 nM estradiol (detection ofestrogen antagonist activity).

[1030] The cells were cultured in the presence of test compounds for 24hours at 37° C. and under a 5% CO₂ atmosphere. Cell proliferation wasdetected by measuring the level of BrdU incorporation into DNA. This wasaccomplished using a commercially available reagent kit (BoeringerMannheim/Roche). The assay was run according to the manufacturersdirection. Ten microliters of BrDU labeling reagent, diluted accordingto the manufacturers directions, was added directly into each well, andincubation was continued for four hours. The culture media was thenaspirated from the wells, and 100 μl of the fixing/denaturing agent fromthe kit was added. The cells were fixed for 30 minutes at roomtemperature. The plates were aspirated again, and 100 μl ofperoxidase-labeled anti-BrdU antibody from the kit was added to eachwell. After one hour, the plates were washed six times with phosphatebuffered saline (“PBS”), and 100 μl of SUPERSIGNAL (a chemilumiscentperoxidase substrate, Pierce Chemical) was added. The plates were shakenfor ten minutes at room temperature, and the resulting chemiluminescentsignals were counted using a TR₁ LUX scintillation counter. Threecompounds of the invention, 4- {4-ethyl-5-(4-hydroxyphenyl)1-[2-(trifluoromethyl)phenyl]pyrazol-3-yl} phenol and 4-[1-cyclobutyl-4-ethyl-5-(4-hydroxyphenyl)pyrazol-3-yl]phenol, were testedusing the above-described protocol and demonstrated activity at lessthan one hundred nanomolar concentrations.

[1031] Thus, the present invention will be seen to provide new compoundsthat have strong estrogen receptor-modulating action. These compoundscan be employed in compositions and methods for treating estrogenreceptor-mediated disorders, such as osteoporosis, breast andendometrial cancer, Alzheimer's disease, and atherosclerosis.

[1032] The disclosure above is for the purposes of illustration and notlimitation. Those having skill in the arts relevant to the presentinvention (e.g., the organic chemistry, medicinal chemistry,endocrinology, and medical arts) will appreciate from the foregoing thepresent invention encompasses many additional embodiments of theinvention that are not described explicitly, but which nevertheless areprovided by the teachings of the present invention. Such additionalembodiments include, but are not limited to, estrogen receptor-mediateddiseases other than osteoporosis, breast and endometrial cancer,Alzheimer's disease, and atherosclerosis, that are preventable ortreatable using the compounds, compositions, and methods of theinvention. Still other aspects include compounds that can be designed,synthesized, and tested for therapeutic or prophylactic effect using theteachings of the foregoing disclosure. 6 Bibliography

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[1084] Wilson, T. M., J. D. Norris, et al. 1997. “Dissection of theMolecular Mechanism of Action of GW5638, a Novel Estrogen ReceptorLigand, Provides Insights into the Role of Estrogen Receptor InBone.”Endocrinology 138(9): 3901-3911.

[1085] Wilson, T. M. 1997. “Non-Steroidal Ligands for the EstrogenReceptor”. U.S. Pat. No.: 5,681,835. Oct. 28, 1997.

[1086] Wilson, T. M. 1999. “Non-Steroidal Ligands for the EstrogenReceptor”. U.S. Pat. No.: 5,977,219. Mar. 2, 1999.

1. A compound having a formula selected from the group consisting of:

and their pharmaceutically acceptable salts, wherein: R₁ and R₃ areselected independently from the group consisting of optionallysubstituted loweralkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl,aralkyl, heteroaralkyl, (cycloalkyl)alkyl, and (cycloheteroalkyl)alkylR₂ is selected from the group consisting of hydrogen, halo, cyano,nitro, thio, amino, carboxyl, formyl, and optionally substitutedloweralkyl, loweralkylcarbonyloxy, arylcarbonyloxy,heteroarylcarbonyloxy, cycloalkylcarbonyloxy,cycloheteroalkylcarbonyloxy, aralkycarbonyloxy,heteroaralkylcarbonyloxy, (cycloalkyl)alkylcarbonyloxy,(cycloheteroalkyl)alkylcarbonyloxy, loweralkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, cycloalkylcarbonyl, cycloheteroalkylcarbonyl,aralkycarbonyl, heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl,(cycloheteroalkyl)alkylcarbonyl, loweralkylaminocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl,heteroaralkylaminocarbonyl, cycloalkylaminocarbonyl,(cycloalkyl)alkylaminocarbonyl, cycloheteroalkylaminocarbonyl,(cycloheteroalkyl)alkylaminocarbonyl, loweralkylcarbonylamino,arylcarbonylamino, heteroarylcarbonylamino, cycloalkylcarbonylamino,cycloheteroalkylcarbonylamino, aralkylcarbonylamino,heteroaralkylcarbonylamino, (cycloalkyl)alkylcarbonylamino,(cycloheteroalkyl)alkylcarbonylamino, loweralkylamino, arylamino,aralkylamino, heteroarylamino, heteroaralkylamino, loweralkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl,cycloheteroalkylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl,(cycloalkyl)alkylsulfonyl, (cycloheteroalkyl)alkylsulfonyl,loweralkylsulfinyl, arylsulfinyl, heteroarylsulfinyl,cycloalkylsulfinyl, cycloheteroalkylsulfinyl, aralkylsulfinyl,heteroaralkylsulfinyl, (cycloalkyl)alkylsulfinyl,(cycloheteroalkyl)alkylsulfinyl, loweralkyloxy, aryloxy, heteroaryloxy,cycloalkyloxy, cycloheteroalkyloxy, aralkyloxy, heteroaralkyloxy,(cycloalkyl)alkyloxy, and (cycloheteroalkyl)alkyloxy, loweralkylthio,arylthio, heteroarylthio, cycloalkylthio, cycloheteroalkylthio,aralkylthio, heteroaraLkylthio, (cycloalkyl)alkylthio,(cycloheteroalkyl)alkylthio, loweralkylthiocarbonyl, arylthiocarbonyl,heteroarylthiocarbonyl, cycloalkylthiocarbonyl,cycloheteroalkylthiocarbonyl, aralkythiocarbonyloxythiocarbonyl,heteroaralkylthiocarbonyl, (cycloalkyl)alkylthiocarbonyl,(cycloheteroalkyl)alkylthiocarbonyl, loweralkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, cycloalkyloxycarbonyl,cycloheteroalkyloxycarbonyl, aralkyoxycarbonyloxloxycarbonyl,heteroaralkyloxycarbonyl, (cycloalkyl)alkyloxycarbonyl,(cycloheteroalkyl)alkyloxycarbonyl, iminoloweralkyl, iminocycloalkyl,iminocycloheteroalkyl, iminoaralkyl, iminoheteroaralkyl,(cycloalkyl)iminoalkyl, (cycloheteroalkyl)iminoalkyl,(cycloiminoalkyl)alkyl, (cycloiminoheteroalkyl)alkyl, oximinoloweralkyl,oximinocycloalkyl, oximinocycloheteroalkyl, oximinoaralkyl,oximinoheteroaralkyl, (cycloalkyl)oximinoalkyl,(cyclooximinoalkyl)alkyl, (cyclooximinoheteroalkyl)alkyl, and(cycloheteroalkyl)oximinoalkyl; and R₄ is selected from the groupconsisting of hydrogen, carboxyl, formyl, and optionally substitutedloweralkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl,cycloheteroalkyl, loweralkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,cycloalkylcarbonyl, cycloheteroalkylcarbonyl, aralkycarbonyl,heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl,(cycloheteroalkyl)alkylcarbonyl, loweralkylaminocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl,heteroaralkylaminocarbonyl, cycloalkylaminocarbonyl,(cycloalkyl)alkylamninocarbonyl, cycloheteroalkylaminocarbonyl,(cycloheteroalkyl)alkylaminocarbonyl, loweralkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl, cycloheteroalkylsulfonyl,aralkylsulfonyl, heteroaralkylsulfonyl, (cycloalkyl)alkylsulfonyl,(cycloheteroalkyl)alkylsulfonyl, loweralkylsulfinyl, arylsulfinyl,heteroarylsulfinyl, cycloalkylsulfinyl, cycloheteroalkylsulfinyl,aralkylsulfinyl, heteroaralkylsulfinyl, (cycloalkyl)alkylsulfinyl,(cycloheteroalkyl)alkylsulfmiyl, arylthiocarbonyl,heteroarylthiocarbonyl, cycloalkylthiocarbonyl,cycloheteroalkylthiocarbonyl, aralkytiocarbonyloxythiocarbonyl,heteroaralkylthiocarbonyl, (cycloalkyl)alkylthiocarbonyl,(cycloheteroalkyl)alkylthiocarbonyl, loweralkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, cycloalkyloxycarbonyl,cycloheteroalkyloxycarbonyl, aralkyoxycarbonyloxloxycarbonyl,heteroaralkyloxycarbonyl, (cycloalkyl)alkyloxycarbonyl,(cycloheteroalkyl)alkyloxycarbonyl, carboxamidino,loweralkylcarboxamidino, arylcarboxamidino, aralkylcarboxamidino,heteroarylcarboxamidino, heteroaralkylcarboxamidino,cycloalkylcarboxamidino, cycloheteroalkylcarboxamindino.
 2. The compoundof claim 1, wherein R₁ and R₃ are selected independently from the groupconsisting of optionally substituted cycloalkyl, cycloheteroalkyl,(cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl.
 3. The compound of claim1, wherein R₁ and R₃ are selected independently from the groupconsisting of optionally substituted aryl, heteroaryl, aralkyl, andheteroaralkyl.
 4. The compound of claim 3, wherein R₁ and R₃ areselected independently from the group consisting of optionallysubstituted heteroaryl and heteroaralkyl.
 5. The compound of claim 3,wherein R₁ and R₃ are selected independently from the group consistingof optionally substituted aryl and aralkyl.
 6. The compound of claim 5,wherein at least one of R₁ and R₃ is substituted with at least onehydroxyl, alkyloxy, aryloxy, thio, alkylthio, or arylthio group.
 7. Thecompound of claim 6, wherein at least one of R₁ and R₃ is selectedindependently from the group consisting of phenyl, phenyloxyloweralkyl,and phenylloweralkyl.
 8. The compound of claim 7, wherein at least oneof R₁ and R₃ is substituted optionally with a substituent selected fromthe group consisting of halogen, nitro, cyano, loweralkyl,haloloweralkyl, loweralkyloxy, haloloweralkyloxy, carboxy,loweralkyloxycarbonyl, aryloxycarbonyl, (cycloloweralkyl)oxycarbonyl,aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl,(heterocycloloweralkyl)oxycarbonyl, loweralkylsulfinyl,loweralkylsulfonyl, loweralkylthio, arylthio, loweralkylcarbonyloxy,arylcarbonyloxy, aralkycarbonyloxy, heteroarylcarbonyloxy,heteroaralkylcarbonyloxy, (cycloloweralkyl)carbonyloxy,alkylsulfonylamino, (heterocycloloweralkyl)carbonyloxy, aminocarbonyl,loweraklylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl,heteroarylaminocarbonyl, and heteroaralkylaminocarbonyl.
 9. The compoundof claim 8, wherein at least one of R₁ and R₃ is substituted optionallywith a substituent selected from the group consisting of halogen, nitro,cyano, loweralkyl, haloloweralkyl, loweralkyloxy, halolowerlakyloxy,carboxy, loweralkylthio, aminocarbonyl, and loweralkylsulfinyl.
 10. Thecompound of claim 1, wherein R₂ is selected from the group consisting ofhydrogen, halo, and optionally substituted loweralkyl, haloloweralkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxyalkyl, arylthioalkyl,arylcarbonyl, heteroarylcarbonyl, loweralkylcarbonyl, aminocarbonyl,arylaminocarbonyl, loweralkylaminocarbonyl, aralkylaminocarbonyl,(eterocycloloweralkyl)alkylaminocarbonyl, heteroarylaminocarbonyl,heteroaralkylaminocarbonyl, (cycloloweralkyl)aminocarbonyl, formyl, andalkenyl.
 11. The compound of claim 10, wherein R₂ is selected from thegroup consisting of hydrogen and halo.
 12. The compound of claim 10,wherein R₂ is selected from the group consisting of optionallysubstituted phenyl, phenylloweralkyl, hydroxyphenyl,loweralkyloxyphenyl, haloloweralkylsulfonylloweralkyloxyphenyl,diloweralkylaminoloweralkyloxyphenyl,(cycloaminoloweralkyl)loweralkyloxyphenyl, and(heterocycloalkyl)loweralkyloxyphenyl.
 13. The compound of claim 10,wherein R₂ is selected from the group consisting of optionallysubstituted loweralkyl, haloloweralkyl, hydroxyalkyl,phenyloxyloweralkyl, hydroxyphenyloweralkyl,haloloweralkylsulfonylloweralkyl, and phenylthioloweralkyl.
 14. Thecompound of claim 10, wherein R₂ is selected from the group consistingof optionally substituted phenylcarbonyl,(heterocycloalkyl)loweralkyloxyphenylcarbonyl, hydroxyphenylcarbonyl,halophenylcarbonyl, phenylloweralkylaninocarbonyl,diloweralkylaminocarbonyl, phenylloweralkylaminocarbonyl,hydroxyphenyllowerlakylaminocarbonyl, cycloalkylaminocarbonyl,loweralkylphenylcarbonyl,haloloweralkylsulfonylloweralkyloxyphenylcarbonyl, andnitrophenylcarbonyl.
 15. The compound of claim 14, wherein R₁ and R₃ areselected independently from the group consisting of optionallysubstituted cycloalkyl, cycloheteroalkyl, (cycloalkyl)alkyl, and(cycloheteroalkyl)alkyl.
 16. The compound of claim 15, wherein R₁ and R₃are selected independently from the group consisting of optionallysubstituted aryl, heteroaryl, aralkyl, and heteroaralkyl.
 17. Thecompound of claim 16, wherein R₁ and R₃ are selected independently fromthe group consisting of optionally substituted aryl and aralkyl.
 18. Thecompound of claim 17, wherein at least one of R₁ and R₃ is substitutedwith at least one hydroxyl or thio group.
 19. The compound of claim 18,wherein at least one of R₁ and R₃ is selected independently from thegroup consisting of phenyl, phenyloxyloweralkyl, and phenylloweralkyl.20. The compound of claim 20, wherein at least one of R₁ and R₃ issubstituted optionally with a substituent selected from the groupconsisting of halogen, loweralkyl, haloloweralkyl, loweralkyloxy,halolowerlakyloxy, carboxy, loweralkyloxycarbonyl, aryloxycarbonyl,(cycloloweralkyl)oxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl,heteroaralkyloxycarbonyl, (heterocycloloweralkyl)oxycarbonyl,loweralkylsulfinyl, loweralkylsulfonyl, loweralkylthio, arylthio,loweralkylcarbonyloxy, arylcarbonyloxy, aralkycarbonyloxy,heteroarylcarbonyloxy, heteroaralkylcarbonyloxy,(cycloloweralkyl)carbonyloxy, (heterocycloloweralkyl)carbonyloxy,aminocarbonyl, loweraklylaminocarbonyl, arylaminocarbonyl,aralkylaminocarbonyl, heteroarylaminocarbonyl, andheteroaralkylaminocarbonyl.
 21. The compound of claim 20, wherein R₄ isselected from the group consisting of hydrogen and optionallysubstituted loweralkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,cycloalkyl, cycloheteroalkyl, loweralkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, cycloalkylcarbonyl, cycloheteroalkylcarbonyl,aralkycarbonyl, heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl,(cycloheteroalkyl)alkylcarbonyl, loweralkylaminocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl,heteroaralkylaminocarbonyl, cycloalkylamninocarbonyl,(cycloalkyl)alkylaminocarbonyl, cycloheteroalkylaminocarbonyl,(cycloheteroalkyl)alkylaminocarbonyl, loweralkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl, cycloheteroalkylsulfonyl,aralkylsulfonyl, heteroaralkylsulfonyl, (cycloalkyl)alkylsulfonyl, and(cycloheteroalkyl)alkylsulfonyl.
 22. A compound having the formulaselected from the group consisting of:

and their pharmaceutically acceptable salts, wherein: X₅ is —(X₁₀)_(n)-,wherein n is an integer between 1 and 3 and X₁₀, for each value of n, isselected independently from the group consisting of oxygen, -SO_(X)-where x is and integer between 0 and 2, nitrogen, nitrogen substitutedwith optionally substituted loweralkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, arylcarbonyl, alkylcarbonyl, aralkylcarbonyl,heteroarylcarbonyl, heteroaralkylcarbonyl, and methylene or methine,each optionally substituted from the group consisting of halo, cyano,nitro, thio, amino, carboxyl, formyl, and optionally substitutedloweralkyl, loweralkylcarbonyloxy, arylcarbonyloxy,heteroarylcarbonyloxy, cycloalkylcarbonyloxy,cycloheteroalkylcarbonyloxy, aralkycarbonyloxy,heteroaralkylcarbonyloxy, (cycloalkyl)alkylcarbonyloxy,(cycloheteroalkyl)alkylcarbonyloxy, loweralkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, cycloalkylcarbonyl, cycloheteroalkylcarbonyl,aralkycarbonyl, heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl,(cycloheteroalkyl)alkylcarbonyl, loweralkylaminocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl,heteroaralkylaminocarbonyl, loweralkylcarbonylamino, arylcarbonylamino,heteroarylcarbonylamino, cycloalkylcarbonylamino,cycloheteroalkylcarbonylamino, aralkylcarbonylamino,heteroaralkylcarbonylamino, (cycloalkyl)alkylcarbonylamino,(cycloheteroalkyl)alkylcarbonylamino, loweralkylamino, arylamino,aralkylamino, heteroarylamino, heteroaralkylamino, loweralkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl,cycloheteroalkylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl,(cycloalkyl)alkylsulfonyl, (cycloheteroalkyl)alkylsulfonyl,loweralkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, cycloalkylsulfnyl,cycloheteroalkylsulfinyl, aralkylsulfinyl, heteroaralkylsulfinyl,(cycloalkyl)alkylsulfinyl, (cycloheteroalkyl)alkylsulfinyl,loweralkyloxy, aryloxy, heteroaryloxy, cycloalkyloxy,cycloheteroalkyloxy, aralkyloxy, heteroaralkyloxy, (cycloalkyl)alkyloxy,and (cycloheteroalkyl)alkyloxy, loweralkylthio, arylthio,heteroarylthio, cycloalkylthio, cycloheteroalkylthio, aralkylthio,heteroaralkylthio, (cycloalkyl)alkylthio, (cycloheteroalkyl)alkylthio,loweralkylthiocarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl,cycloalkylthiocarbonyl, cycloheteroalkylthiocarbonyl,arallythiocarbonyloxlthiocarbonyl, heteroaralkylthiocarbonyl,(cycloalkyl)alkylthiocarbonyl, (cycloheteroalkyl)alkylthiocarbonyl,loweralkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,cycloalkyloxycarbonyl, cycloheteroalkyloxycarbonyl,aralkyoxycarbonyloxloxycarbonyl, heteroaralkyloxycarbonyl,(cycloalkyl)alkyloxycarbonyl, (cycloheteroalkyl)alkyloxycarbonyl,iminoloweralkyl, iminocycloalkyl, iminocycloheteroalkyl, iminoaralkyl,iminoheteroaralkyl, (cycloalkyl)iminoalkyl, and(cycloheteroalkyl)iminoalkyl; X₆—X₉ are selected independently from thegroup consisting of oxygen, sulfur, sulfinyl, nitrogen, and optionallysubstituted methine; R₅ is selected from the group consisting ofhydrogen, carboxyl, formyl, and optionally substituted loweralkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloheteroalkyl,loweralkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,cycloalkylcarbonyl, cycloheteroalkylcarbonyl, aralkycarbonyl,heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl,(cycloheteroalkyl)alkylcarbonyl, loweralkylaninocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocartbonyl,heteroaralkylaninocarbonyl, cycloalkylaminocarbonyl,(cycloalkyl)alkylaminocarbonyl, cycloheteroalkylaminocarbonyl,(cycloheteroalkyl)alkylaminocarbonyl, loweralkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl, cycloheteroalkylsulfonyl,aralkylsulfonyl, heteroaralkylsulfonyl, (cycloalkyl)alkylsulfonyl,(cycloheteroalkyl)alkylsulfonyl, loweralkylsulfinyl, arylsulfinyl,heteroarylsulfinyl, cycloalkylsulfinyl, cycloheteroalkylsulfinyl,aralkylsulfinyl, heteroaralkylsulfinyl, (cycloalkyl)alkylsulfinyl,(cycloheteroalkyl)alkylsulfinyl, arylthiocarbonyl,heteroarylthiocarbonyl, cycloalkylthiocarbonyl,cycloheteroalkylthiocarbonyl, aralkythiocarbonyloxythiocarbonyl,heteroaralkylthiocarbonyl, (cycloalkyl)alkylthiocarbonyl,(cycloheteroalkyl)alkylthiocarbonyl, loweralkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, cycloalkyloxycarbonyl,cycloheteroalkyloxycarbonyl, aralkyoxycarbonyloxloxycarbonyl,heteroaralkyloxycarbonyl, (cycloalkyl)alkyloxycarbonyl,(cycloheteroalkyl)alkyloxycarbonyl, carboxamidino,loweralkylcarboxamidino, arylcarboxamidino, aralkylcarboxamidino,heteroarylcarboxamidino, heteroaralkylcarboxamidino,cycloalkylcarboxamidino, cycloheteroalkylcarboxamnindino and R₆ isselected from the group consisting of optionally substituted loweralkyl,aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, aralkyl, heteroaralkyl,(cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl.
 23. The compound ofclaim 22, wherein n is 1 and X₁₀ is selected from the group consistingof nitrogen, optionally substituted nitrogen, and optionally substitutedmethylene or methine.
 24. The compound of claim 23, wherein R₆ isselected from the group consisting of optionally substituted aryl,heteroaryl, aralkyl, and heteroaralkyl.
 25. The compound of claim 24,wherein R₆ is optionally substituted aryl or aralkyl.
 26. The compoundof claim 25, wherein R₆ includes at least one hydroxyl, thio, oroptionally substituted loweralkyloxy, aryloxy, heteroaryloxy,loweralkylthio, arylthio, heteroarylthio, loweralkylcarbonyl,arylcarbonyl, or heteroarylcarbonyl moiety.
 27. The compound of claim26, wherein R₆ is selected from the group consisting of phenyl,phenyloxyloweralkyl, and phenylloweralkyl.
 28. The compound of claim 27,wherein R₆ is further substituted optionally with a moiety selected fromthe group consisting of halogen, loweralkyl, haloloweralkyl,loweralkyloxy, halolowerlakyloxy, carboxy, loweralkyloxycarbonyl,aryloxycarbonyl, (cycloloweralkyl)oxycarbonyl, aralkyloxycarbonyl,heteroaryloxycarbonyl, heteroaralkyloxycarbonyl,(heterocycloloweralkyl)oxycarbonyl, loweralkylsulfinyl,loweralkylsulfonyl, loweralkylthio, arylthio, loweralkylcarbonyloxy,arylcarbonyloxy, aralkycarbonyloxy, heteroarylcarbonyloxy,heteroaralkylcarbonyloxy, (cycloloweralkyl)carbonyloxy,(heterocycloloweralkyl)carbonyloxy, aminocarbonyl,loweraklylaminocarbonyl, arylaminocarbonyl, aralkylaninocarbonyl,heteroarylaminocarbonyl, and heteroaralkylaminocarbonyl.
 29. Thecompound of claim 28, wherein R₅ is selected from the group consistingof hydrogen and optionally substituted loweralkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, cycloalkyl, cycloheteroalkyl,loweralkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,cycloalkylcarbonyl, cycloheteroalkylcarbonyl, aralkycarbonyl,heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl,(cycloheteroalkyl)alkylcarbonyl, loweralkylaninocarbonyl,arylaninocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl,heteroaralkylaminocarbonyl, cycloalkylaminocarbonyl,(cycloalkyl)alkylaminocarbonyl, cycloheteroalkylaminocarbonyl,(cycloheteroalkyl)alkylaminocarbonyl, loweralkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl, cycloheteroalkylsulfonyl,aralkylsulfonyl, heteroaralkylsulfonyl, (cycloalkyl)alkylsulfonyl, and(cycloheteroalkyl)alkylsulfonyl.
 30. The compound of claim 22, wherein nis 2 and each X₁₀is selected independently from the group consisting ofnitrogen, optionally substituted nitrogen, optionally substitutedmethylene, and optionally substituted methine.
 31. The compound of claim30, wherein R₆ is selected from the group consisting of optionallysubstituted aryl, heteroaryl, aralkyl, and heteroaralkyl.
 32. Thecompound of claim 31, wherein R₆ is optionally substituted aryl oraralkyl.
 33. The compound of claim 32, wherein R₆ includes at least onehydroxyl, thio, or optionally substituted loweralkyloxy, aryloxy,heteroaryloxy, loweralkylthio, arylthio, heteroarylthio,loweralkylcarbonyl, arylcarbonyl, or heteroarylcarbonyl moiety.
 34. Thecompound of claim 33, wherein R₆ is selected from the group consistingof phenyl, phenyloxyloweralkyl, and phenylloweralkyl.
 35. The compoundof claim 34, wherein R₆ is further substituted optionally with a moietyselected from the group consisting of halogen, loweralkyl,haloloweralkyl, loweralkyloxy, halolowerlakyloxy, carboxy,loweralkyloxycarbonyl, aryloxycarbonyl, (cycloloweralkyl)oxycarbonyl,aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl,(heterocycloloweralkyl)oxycarbonyl, loweralkylsulfinyl,loweralkylsulfonyl, loweralkylthio, arylthio, loweralkylcarbonyloxy,arylcarbonyloxy, aralkycarbonyloxy, heteroarylcarbonyloxy,heteroaralkylcarbonyloxy, (cycloloweralkyl)carbonyloxy,(heterocycloloweralkyl)carbonyloxy, amiinocarbonyl,loweraklylamiinocarbonyl, arylamrinocarbonyl, aralkylaminocarbonyl,heteroarylaminocarbonyl, and heteroaralkylaminocarbonyl.
 36. Thecompound of claim 35, wherein R₅ is selected from the group consistingof hydrogen and optionally substituted loweralkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, cycloalkyl, cycloheteroalkyl,loweralkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,cycloalkylcarbonyl, cycloheteroalkylcarbonyl, aralkycarbonyl,heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl,(cycloheteroalkyl)alkylcarbonyl, loweralkylaminocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl,heteroaralkylaminocarbonyl, cycloalkylaminocarbonyl,(cycloalkyl)alkylaminocarbonyl, cycloheteroalkylaminocarbonyl,(cycloheteroalkyl)alkylaminocarbonyl, loweralkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl, cycloheteroalkylsulfonyl,aralkylsulfonyl, heteroaralkylsulfonyl, (cycloalkyl)alkylsulfonyl, and(cycloheteroalkyl)alkylsulfonyl.
 37. The compound of claim 22, whereinX₆—X₉ are selected independently from the group consisting of nitrogenand optionally substituted methine.
 38. The compound of claim 37,wherein at least one of X₆—X₉ is methine substituted with a moietyselected from the group consisting of loweralkyloxy, aryloxy,heteroaryloxy, loweralkylthio, arylthio, heteroarylthio,loweralkylcarbonyl, arylcarbonyl, and heteroarylcarbonyl.
 39. Thecompound of claim 38, wherein X₇ is methine substituted with hydroxy orloweralkyloxy.
 40. The compound of claim 38, wherein n is 1 and X₁₀ isselected from the group consisting of nitrogen, optionally substitutednitrogen, and optionally substituted methylene or methine.
 41. Thecompound of claim 40, wherein R₆ is selected from the group consistingof optionally substituted aryl, heteroaryl, aralkyl, and heteroaralkyl.42. The compound of claim 41, wherein R₆ is optionally substituted arylor aralkyl.
 43. The compound of claim 42, wherein R₆ includes at leastone hydroxyl, thio, or optionally substituted loweralkyloxy, aryloxy,heteroaryloxy, loweralkylthio, arylthio, heteroarylthio,loweralkylcarbonyl, arylcarbonyl, or heteroarylcarbonyl moiety.
 44. Thecompound of claim 43, wherein R₆ is selected from the group consistingof phenyl, phenyloxyloweralkyl, and phenylloweralkyl.
 45. The compoundof claim 44, wherein & is further substituted optionally with a moietyselected from the group consisting of halogen, loweralkyl,haloloweralkyl, loweralkyloxy, halolowerlakyloxy, carboxy,loweralkyloxycarbonyl, aryloxycarbonyl, (cycloloweralkyl)oxycarbonyl,aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl,(heterocycloloweralkyl)oxycarbonyl, loweralkylsulfinyl,loweralkylsulfonyl, loweralkylthio, arylthio, loweralkylcarbonyloxy,arylcarbonyloxy, aralkycarbonyloxy, heteroarylcarbonyloxy,heteroaralkylcarbonyloxy, (cycloloweralkyl)carbonyloxy,(heterocycloloweralkyl)carbonyloxy, aminocarbonyl,loweraklylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl,heteroarylaminocarbonyl, and heteroaralkylaminocarbonyl.
 46. Thecompound of claim 45, wherein R₅ is selected from the group consistingof hydrogen and optionally substituted loweralkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, cycloalkyl, cycloheteroalkyl,loweralkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,cycloalkylcarbonyl, cycloheteroalkylcarbonyl, aralkycarbonyl,heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl,(cycloheteroalkyl)alkylcarbonyl, loweralkylaminocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl,heteroaralkylaminocarbonyl, cycloalkylaminocarbonyl,(cycloalkyl)alkylaminocarbonyl, cycloheteroalkylaminocarbonyl,(cycloheteroalkyl)alkylaminocarbonyl, loweralkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl, cycloheteroalkylsulfonyl,aralkylsulfonyl, heteroaralkylsulfonyl, (cycloalkyl)alkylsulfonyl, and(cycloheteroalkyl)alkylsulfonyl.
 47. The compound of claim 37, wherein nis 2 and each X₁₀is selected independently from the group consisting ofnitrogen, optionally substituted nitrogen, optionally substitutedmethylene, and optionally substituted methine.
 48. The compound of claim47, wherein R₆ is selected from the group consisting of optionallysubstituted aryl, heteroaryl, aralkyl, and heteroaralkyl.
 49. Thecompound of claim 48, wherein R₆ is optionally substituted aryl oraralkyl.
 50. The compound of claim 49, wherein R₆ includes at least onehydroxyl, thio, or optionally substituted loweralkyloxy, aryloxy,heteroaryloxy, loweralkylthio, arylthio, heteroarylthio,loweralkylcarbonyl, arylcarbonyl, or heteroarylcarbonyl moiety.
 51. Thecompound of claim 50, wherein R₆ is selected from the group consistingof phenyl, phenyloxyloweralkyl, and phenylloweralkyl.
 52. The compoundof claim 51, wherein R₆ is further substituted optionally with a moietyselected from the group consisting of halogen, loweralkyl,haloloweralkyl, loweralkyloxy, halolowerlakyloxy, carboxy,loweralkyloxycarbonyl, aryloxycarbonyl, (cycloloweralkyl)oxycarbonyl,aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl,(heterocycloloweralkyl)oxycarbonyl, loweralkylsulfinyl,loweralkylsulfonyl, loweralkylthio, arylthio, loweralkylcarbonyloxy,arylcarbonyloxy, aralkycarbonyloxy, heteroarylcarbonyloxy,heteroaralkylcarbonyloxy, (cycloloweralkyl)carbonyloxy,(heterocycloloweralkyl)carbonyloxy, aminocarbonyl,loweraklylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl,heteroarylaminocarbonyl, and heteroaralkylaminocarbonyl.
 53. Thecompound of claim 51, wherein R₅ is selected from the group consistingof hydrogen and optionally substituted loweralkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, cycloalkyl, cycloheteroalkyl,loweralkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,cycloalkylcarbonyl, cycloheteroalkylcarbonyl, aralkycarbonyl,heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl,(cycloheteroalkyl)alkylcarbonyl, loweralkylaninocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl,heteroaralkylaminocarbonyl, cycloalkylaminocarbonyl,(cycloalkyl)alkylaminocarbonyl, cycloheteroalkylaminocarbonyl,(cycloheteroalkyl)alkylaminocarbonyl, loweralkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, cycloalkylsulfonyl, cycloheteroalkylsulfonyl,aralkylsulfonyl, heteroaralkylsulfonyl, (cycloalkyl)alkylsulfonyl, and(cycloheteroalkyl)alkylsulfonyl.
 54. A composition for use in treatingan estrogen receptor-mediated disorder in a mammal, comprising atherapeutically effective amount of a compound of claim 1 in apharmaceutically effective carrier.
 55. A composition for use intreating an estrogen receptor-mediated disorder in a mammal, comprisinga therapeutically effective amount of a compound of claim 22 in apharmaceutically effective carrier.
 56. A method for treating anestrogen receptor-mediated disorder in a mammal, comprisingadministering to such mammal a therapeutically effective amount of acompound of claim 1 in a pharmaceutically effective carrier.
 57. Themethod of claim 56, wherein said disease is chosen from the groupconsisting of: osteoporosis, estrogen-dependent cancer, Alzbeimer'sdisease, and estrogen-dependent illness.
 58. A method for treating anestrogen receptor-mediated disorder in a mammal, comprisingadministering to such mammal a therapeutically effective amount of acompound of claim 22 in a pharmaceutically effective carrier.
 59. Themethod of claim 58, wherein said disease is chosen from the groupconsisting of: osteoporosis, estrogen-dependent cancer, andestrogen-dependent illness.
 60. A method for preventing an estrogenreceptor-mediated disorder in a mammal, comprising administering to suchmammal a prophylactically effective amount of a compound of claim 1 in apharmaceutically effective carrier.
 61. The method of claim 60, whereinsaid disease is chosen from the group consisting of: osteoporosis,estrogen-dependent cancer, Alzheimer's disease and estrogen-dependentillness.
 62. A method for preventing an estrogen receptor-mediateddisorder in a mammal, comprising administering to such mammal aprophylactically effective amount of a compound of claim 22 in apharmaceutically effective carrier.
 63. The method of claim 62, whereinsaid disease is chosen from the group consisting of: osteoporosis,estrogen-dependent cancer, and estrogen-dependent illness.
 64. A methodfor modulating the biological activity of an estrogen receptor,comprising exposing said estrogen receptor to a compound of claim 1 tomodulate thereby the binding of said estrogen receptor to an associatedestrogen receptor element.
 65. The method of claim 64, wherein saidestrogen receptor is the α isoform.
 66. The method of claim 64, whereinsaid estrogen receptor is the β isoform.
 67. A method for modulating thebiological activity of an estrogen receptor, comprising exposing saidestrogen receptor to a compound of claim 22 to modulate thereby thebinding of said estrogen receptor to an associated estrogen receptorelement.
 68. The method of claim 67, wherein said estrogen receptor isthe α isoform.
 69. The method of claim 67, wherein said estrogenreceptor is the β isoform.